Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state

ABSTRACT

Oral pharmaceutical compositions of sodium oxybate having improved pharmacokinetic properties when administered less than two hours after eating are provided, and therapeutic uses thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/804,966, filed Feb. 28, 2020, which claims priority to U.S.Provisional Application No. 62/812,699, filed Mar. 1, 2019 and U.S.Provisional Application No. 62/857,008, filed Jun. 4, 2019.

FIELD

The present invention relates to compositions for the treatment ofnarcolepsy, cataplexy, or excessive daytime sleepiness comprisinggamma-hydroxybutyrate in a unit dose suitable for administration lessthan two hours after eating. The present invention also relates tomodified release formulations of gamma-hydroxybutyrate having improvedpharmacokinetic (PK) properties in the fed state, and to therapeuticuses thereof.

BACKGROUND

Narcolepsy is a devastating disabling condition. The cardinal symptomsare excessive daytime sleepiness (EDS), cataplexy (a sudden loss ofmuscle tone triggered by strong emotions, seen in approximately 60% ofpatients), hypnogogic hallucination (HH), sleep paralysis (SP), anddisturbed nocturnal sleep (DNS). Other than EDS, DNS is the most commonsymptom seen among narcolepsy patients.

One of the major treatments for narcolepsy is sodium oxybate. Theprecise mechanism by which sodium oxybate produces an effect is unknown,however sodium oxybate is thought to act by promoting SWS (delta sleep)and consolidating night-time sleep. Sodium oxybate administered beforenocturnal sleep increases Stages 3 and 4 sleep and increases sleeplatency, while reducing the frequency of sleep onset REM periods(SOREMPs). Other mechanisms, which have yet to be elucidated, may alsobe involved.

Sodium oxybate is also known as sodium 4-hydroxybutanoate, orgamma-hydroxybutyric acid sodium salt, and has the following chemicalstructure:

Sodium oxybate is marketed commercially in the United States as Xyrem®.The product is formulated as an immediate release liquid solution thatis taken once immediately before bed, and a second time approximately2.5 to 4 hours later, in equal doses. Sleep-onset may be dramatic andfast, and patients are advised to be sitting in bed when consuming thedose. The most commonly reported side effects are nausea, dizziness,vomiting, somnolence, enuresis and tremor.

One critical drawback of Xyrem® is the requirement to take the firstdoes at least 2 hours after eating. Specifically, Xyrem®'s labelexpressly advises “[t]ake the first dose of Xyrem® at least 2 hoursafter eating because food significantly reduces the bioavailability ofsodium oxybate.” The medical problem cautioned against by the Xyrem®label and unaddressed by the prior art is a deleterious food effect onthe absorption of GHB. As noted in the FDA's Xyrem® Risk ManagementProgram, “Because food significantly reduces the bioavailability ofsodium oxybate, the patient should try to eat well before (severalhours) going to sleep and taking the first dose of sodium oxybate.Patients should try to minimize variability in the timing of dosing inrelation to meals.” (Seehttps://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21196lbl.pdf).As a practical matter, the food effect obstacle of the prior art createsa variety of unmet problems for the patient because it is not alwayspossible to eat several hours before sleep. Likewise, despite bestefforts, a patient may have variability in the timing of dosing inrelation to meals due to unforeseen schedule changes, travel, etc. As aresult, the food effect problem of the prior art necessarily causesreduced patient compliance, reduced efficacy, and reduced safety.Moreover, since GHB is a known drug of abuse, there is inherently agreater risk of abuse, including accidental abuse, as a result ofXyrem®'s food effect problem.

Scientific studies have shown that after a high-fat meal the intestinaluptake of GHB may be significantly decreased due to the inhibition ofanionic transporters, such as the Monocarboxylic Acid Transporters(MCTs). MCTs are transport proteins that determine the absorption, renalclearance, and distribution of GHB throughout the body. Recent studieshave shown the MCT-mediated intestinal absorption of GHB to occur in aconcentration- and proton gradient-dependent manner and via acarrier-mediated process along the length of the intestine. TheMCT-mediated intestinal absorption of GHB is important for itspharmacological activity because more than 99% of GHB is ionized andcannot diffuse across cellular membranes at physiologic pH.

Accordingly, there is a need for compositions of gamma-hydroxybutyratethat can be administered less than two hours after eating withoutcompromising safety or efficacy.

SUMMARY OF THE INVENTION

In an aspect, the present disclosure encompasses an oral pharmaceuticalcomposition for the treatment of narcolepsy, cataplexy, or excessivedaytime sleepiness that may be administered less than two hours aftereating. For example, a composition including gamma-hydroxybutyrate maybe in a unit dose suitable for administration less than two hours aftereating. In additional aspects, the composition may me suitable foronce-daily administration. In some aspects, the composition provides amean AUC_(inf) and/or mean C_(max) when administered less than two hourafter eating that is 50%-120% of the mean AUC_(inf) or mean C_(max) whenthe composition is administered at least two hours after eating. Whenadministered less than two hours after eating, the composition mayprovide an AUC_(inf) and/or a C_(max) bioequivalent to an AUC_(inf) orC_(max) of an equal dose of immediate release liquid solution of sodiumoxybate administered at t₀ and t_(4h) in equally divided doses at leasttwo hours after eating. In some aspects, a 6 g dose of the compositionadministered less than two hours after eating has been shown to achievea mean AUC_(inf) of greater than 240 hr*μ/mL, and a mean C_(max) that isfrom 50% to 140% of the mean C_(max) provided by an equal dose ofimmediate release liquid solution of sodium oxybate administered at t₀and t_(4h) in equally divided doses at least two hours after eating.

Further provided herein is a method of treating narcolepsy andassociated disorders and symptoms in a patient in need thereof byadministering an oral pharmaceutical composition ofgamma-hydroxybutyrate less than two hours after eating. In an aspect,the composition may be administered once-daily. In some aspects, thecomposition may be administered in the morning or the evening aftereating. In other aspects, sleep is includes for at least six consecutivehours.

In additional aspects, a method of treating narcolepsy and associateddisorders and symptoms in a patient in need thereof may includeadministering an oral pharmaceutical composition comprisinggamma-hydroxybutyrate once daily, where the composition is doseproportional. The C_(max) of the composition may be dose proportionalacross one or more of 4.5 g, 7.5 g, and 9 g doses of the composition.

Also provided herein are oral pharmaceutical compositions and methodsthereof for the treatment of narcolepsy, cataplexy, or excessive daytimesleepiness comprising gamma-hydroxybutyrate in a unit dose suitable foradministration once daily, where most adverse events (AEs) occur duringthe Tmax period (around C_(max)). In another aspect, compositions andmethods are provided for the treatment of narcolepsy, cataplexy, orexcessive daytime sleepiness comprising gamma-hydroxybutyrate in a unitdose suitable for administration once daily, wherein most adverse events(AEs) occur close to T_(max), during the C_(max) period. In someembodiments of this aspect, administration of the oral pharmaceuticalcomposition less than two hours after eating may result in fewer AEsthan administration of the oral pharmaceutical composition at least twohours after eating. The oral pharmaceutical composition of someembodiments may have a more favorable safety profile (i.e., fewer AEs)as compared to an equal dose of immediate release liquid solution ofsodium oxybate administered at t₀ and t_(4h) in equally divided doses.

Other aspects and iterations of the invention are described morethoroughly below.

DESCRIPTION OF THE FIGURES

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application with color drawing(s)will be provided by the Office by request and payment of the necessaryfee.

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate several embodiments of theinvention and together with the description serve to explain theprinciples of the invention.

FIG. 1A depicts the qualitative and quantitative structure of theimmediate release (IR) microparticles of gamma-hydroxybutyrate ofExample 1.

FIG. 1B depicts the qualitative and quantitative structure of themodified release (MR) microparticles of gamma-hydroxybutyrate of Example1.

FIG. 2A is a mean concentration versus time curve for 6 g FT218administered in the fed and fasted state.

FIG. 2B is a series of individual profiles in a mean concentrationversus time curve for 6 g FT218 administered in the fed and fastedstate.

FIG. 3A is a simulated concentration versus time curve for 3 g IRmicroparticles of FT218 administered in the fed and fasted state.

FIG. 3B is a simulated concentration versus time curve for 6 g FT218 andIR and MR microparticle portions of FT218 administered in the fed andfasted state.

FIG. 4A is a concentration versus time curve for a 4.5 g single dose ofXyrem® in the fed state, the fasted state and 2 hours post meal.

FIG. 4B is a concentration versus time curve for a 6 g dose of FT218 inthe fed state, the fasted state and 2 hours post meal.

FIG. 5A shows expected concentration versus time curves for two 3 gdoses of Xyrem® and one 6 g dose of FT218 in the fed state.

FIG. 5B shows expected concentration versus time curves for two 3 gdoses of Xyrem® and one 6 g does of FT218 administered two hourspost-meal.

FIG. 5C shows expected concentration versus time curves for two 3 gdoses of Xyrem® and one 6 g dose of FT218 administered in the fastedstate.

FIG. 6A shows expected concentration versus time curves for two 4.5 gdoses of Xyrem® and one 9 g dose of FT218 in the fed state.

FIG. 6B shows expected concentration versus time curves for two 4.5 gdoses of Xyrem® and one 9 g dose of FT218 administered two hourspost-meal.

FIG. 6C shows expected concentration versus time curves for two 4.5 gdoses of Xyrem® and one 9 g dose of FT218 administered in the fastedstate.

FIG. 7A shows AUC versus time after a meal for 6 g FT218 and 6 g Xyrem®.

FIG. 7B shows C_(max) versus time after a meal for 6 g FT218 and 6 gXyrem®.

FIG. 8 shows FT218 plasma concentration time curves for rising dosesfrom 4.5 g to 9 g per night.

DETAILED DESCRIPTION

The present invention may be understood more readily by reference to thefollowing detailed description of embodiments of the formulation,methods of treatment using some embodiments of the formulation, and theExamples included therein.

Definitions and Use of Terms

Wherever an analysis or test is required to understand a given propertyor characteristic recited herein, it will be understood that theanalysis or test is performed in accordance with applicable guidances,draft guidances, regulations and monographs of the United States Foodand Drug Administration (“FDA”) and United States Pharmacopoeia (“USP”)applicable to drug products in the United States in force as of Nov. 1,2015 unless otherwise specified. Clinical endpoints may be judged withreference to standards adopted by the American Academy of SleepMedicine, including standards published at C Iber, S Ancoli-Israel, AChesson, S F Quan. The AASM Manual for the Scoring of Sleep andAssociated Events. Westchester, Ill.: American Academy of SleepMedicine; 2007.

When a pharmacokinetic comparison is made between a formulationdescribed or claimed herein and a reference product, it will beunderstood that the comparison is performed in a suitable designedcross-over trial, although it will also be understood that a cross-overtrial is not required unless specifically stated. It will also beunderstood that the comparison may be made either directly orindirectly. For example, even if a formulation has not been testeddirectly against a reference formulation, it can still satisfy acomparison to the reference formulation if it has been tested against adifferent formulation, and the comparison with the reference formulationmay be deduced therefrom.

As used in this specification and in the claims which follow, thesingular forms “a,” “an” and “the” include plural referents unless thecontext dictates otherwise. Thus, for example, reference to “aningredient” includes mixtures of ingredients, reference to “an activepharmaceutical agent” includes more than one active pharmaceuticalagent, and the like.

“Bioavailability” means the rate and extent to which the activeingredient or active moiety is absorbed from a drug product and becomesavailable at the site of action.

“Relative bioavailability” or “Rel BA” or “RBA” means the percentage ofmean AUC_(inf) of the tested product relative to the mean AUC_(inf) ofthe reference product for an equal total dose. Unless otherwisespecified, relative bioavailability refers to the percentage of the meanAUC_(inf) observed for a full dose of the test product relative to themean AUC_(inf) observed for two ½ doses of an immediate release liquidsolution administered four hours apart for an equal total dose.

“Bioequivalence” means the absence of a significant difference in therate and extent to which the active ingredient or active moiety inpharmaceutical equivalents or pharmaceutical alternatives becomeavailable at the site of drug action when administered at the same molardose under similar conditions in an appropriately designed study.

When ranges are given by specifying the lower end of a range separatelyfrom the upper end of the range, it will be understood that the rangemay be defined by selectively combining any one of the lower endvariables with any one of the upper end variables that is mathematicallyand physically possible. Thus, for example, if a formulation may containfrom 1 to 10 weight parts of a particular ingredient, or 2 to 8 parts ofa particular ingredient, it will be understood that the formulation mayalso contain from 2 to 10 parts of the ingredient. In like manner, if aformulation may contain greater than 1 or 2 weight parts of aningredient and up to 10 or 9 weight parts of the ingredient, it will beunderstood that the formulation may contain 1-10 weight parts of theingredient, 2-9 weight parts of the ingredient, etc. unless otherwisespecified, the boundaries of the range (lower and upper ends of therange) are included in the claimed range.

In like manner, when various sub-embodiments of a senior (i.e.principal) embodiment are described herein, it will be understood thatthe sub-embodiments for the senior embodiment may be combined to defineanother sub-embodiment. Thus, for example, when a principal embodimentincludes sub-embodiments 1, 2 and 3, it will be understood that theprincipal embodiment may be further limited by any one ofsub-embodiments 1, 2 and 3, or any combination of sub-embodiments 1, 2and 3 that is mathematically and physically possible. In like manner, itwill be understood that the principal embodiments described herein maybe combined in any manner that is mathematically and physicallypossible, and that the invention extends to such combinations.

When used herein the term “about” or “substantially” or “approximately”will compensate for variability allowed for in the pharmaceuticalindustry and inherent in pharmaceutical products, such as differences inproduct strength due to manufacturing variation and time-induced productdegradation. The term allows for any variation which in the practice ofpharmaceuticals would allow the product being evaluated to be consideredbioequivalent to the recited strength, as described in FDA's March 2003Guidance for Industry on BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES FORORALLY ADMINISTERED DRUG PRODUCTS—GENERAL CONSIDERATIONS.

When used herein the term “gamma-hydroxybutyrate” or GHB, unlessotherwise specified, refers to the free base of gamma hydroxy-butyrate,a pharmaceutically acceptable salt of gamma-hydroxybutyric acid, andcombinations thereof, their hydrates, solvates, complexes or tautomersforms. Gamma-hydroxybutyric acid salts may be selected from the sodiumsalt of gamma-hydroxybutyric acid or sodium oxybate, the potassium saltof gamma-hydroxybutyric acid, the magnesium salt of gamma-hydroxybutyricacid, the calcium salt of gamma-hydroxybutyric acid, the lithium salt ofgamma-hydroxybutyric, the tetra ammonium salt of gamma-hydroxybutyricacid or any other pharmaceutically acceptable salt forms ofgamma-hydroxybutyric acid.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use. Theterm “formulation” or “composition” refers to the quantitative andqualitative characteristics of a drug product or dosage form prepared inaccordance with the current invention.

As used herein the doses and strengths of gamma-hydroxybutyrate areexpressed in equivalent-gram (g) weights of sodium oxybate unless statedexpressly to the contrary. Thus, when considering a dose ofgamma-hydroxybutyrate other than the sodium salt ofgamma-hydroxybutyrate, one must convert the recited dose or strengthfrom sodium oxybate to the gamma-hydroxybutyrate under evaluation. Thus,if an embodiment is said to provide a 4.5 g dose ofgamma-hydroxybutyrate, because the form of gamma-hydroxybutyrate is notspecified, it will be understood that the dose encompasses a 4.5 g doseof sodium oxybate, a 5.1 g dose of potassium gamma-hydroxybutyrate(assuming a 126.09 g/mol MW for sodium oxybate and a 142.20 g/mol MW forpotassium gamma-hydroxybutyrate), and a 3.7 g dose of the free base(assuming a 126.09 g/mol MW for sodium oxybate and a 104.1 g/mol MW forthe free base of gamma-hydroxybutyrate), or by the weight of any mixtureof salts of gamma-hydroxybutyric acid that provides the same amount ofGHB as 4.5 g of sodium oxybate.

As used herein “microparticle” means any discreet particle of solidmaterial. The particle may be made of a single material or have acomplex structure with core and shells and be made of several materials.The terms “microparticle”, “particle”, “microspheres” or “pellet” areinterchangeable and have the same meaning. Unless otherwise specified,the microparticle has no particular particle size or diameter and is notlimited to particles with volume mean diameter D(4.3) below 1 mm.

As used herein, the “volume mean diameter D(4.3)” is calculatedaccording to the following formula:

D(4,3)=Σ(d4i·ni)/Σ(d3i·ni)

wherein the diameter d of a given particle is the diameter of a hardsphere having the same volume as the volume of that particle.

As used herein, the terms “composition”, “oral composition”, “oralpharmaceutical composition”, “finished composition”, “finishedformulation” or “formulation” are interchangeable and designate thecomposition of gamma-hydroxybutyrate comprising modified releasemicroparticles of gamma-hydroxybutyrate, immediate releasemicroparticles of gamma-hydroxybutyrate, and any other excipients. Thecomposition may be described as extended release, delayed release, ormodified release.

As used herein, “immediate release” means release of the major part ofgamma-hydroxybutyrate over a relatively short period, e.g. at least 75%of the AP is released in 0.75 h, for example, in 30 min.

As used herein, an “immediate release (IR) portion” of a formulationincludes physically discreet portions of a formulation, mechanisticallydiscreet portions of a formulation, and pharmacokinetically discreetportions of a formulation that lend to or support a defined IRpharmacokinetic characteristic. Thus, for example, any formulation thatreleases active ingredient at the rate and extent required of theimmediate release portion of the formulations of the present inventionincludes an “immediate release portion,” even if the immediate releaseportion is physically integrated in what might otherwise be consideredan extended release formulation. Thus, the IR portion may bestructurally discreet or structurally indiscreet from (i.e. integratedwith) the MR portion. In an embodiment, the IR portion and MR portionare provided as particles, and in other embodiments the IR portion andMR portion are provided as particles discreet from each other.

As used here in, “immediate release formulation” or “immediate releaseportion” refers to a composition that releases at least 80% of itsgamma-hydroxybutyrate in 1 hour when tested in a dissolution apparatus 2according to USP 38 <711> in a 0.1N HCl dissolution medium at atemperature of 37° C. and a paddle speed of 75 rpm.

As used herein, “dose dumping” is understood as meaning an immediate andunwanted release of the dose after oral ingestion. In an embodiment,dose dumping may be rapid release of gamma-hydroxybutyrate in thepresence of alcohol.

In like manner, a “modified-release (MR) portion” includes that portionof a formulation or dosage form that lends to or supports a particularMR pharmacokinetic characteristic, regardless of the physicalformulation in which the MR portion is integrated. The modified releasedrug delivery systems are designed to deliver drugs at a specific timeor over a period of time after administration, or at a specific locationin the body. The USP defines a modified release system as one in whichthe time course or location of drug release or both, are chosen toaccomplish objectives of therapeutic effectiveness or convenience notfulfilled by conventional IR dosage forms. More specifically, MR solidoral dosage forms include extended release (ER) and delayed-release (DR)products. A DR product is one that releases a drug all at once at a timeother than promptly after administration. Typically, coatings (e.g.,enteric coatings) are used to delay the release of the drug substanceuntil the dosage form has passed through the acidic medium of thestomach. An ER product is formulated to make the drug available over anextended period after ingestion, thus allowing a reduction in dosingfrequency compared to a drug presented as a conventional dosage form,e.g. a solution or an immediate release dosage form. For oralapplications, the term “extended-release” is usually interchangeablewith “sustained-release”, “prolonged-release” or “controlled-release”.

Traditionally, extended-release systems provided constant drug releaseto maintain a steady concentration of drug. For some drugs, however,zero-order delivery may not be optimal and more complex andsophisticated systems have been developed to provide multi-phasedelivery. One may distinguish among four categories of oral MR deliverysystems: (1) delayed-release using enteric coatings, (2) site-specificor timed release (e.g. for colonic delivery), (3) extended-release(e.g., zero-order, first-order, biphasic release, etc.), and (4),programmed release (e.g., pulsatile, delayed extended release, etc.) SeeModified Oral Drug Delivery Systems at page 34 in Gibaldi's DRUGDELIVERY SYSTEMS IN PHARMACEUTICAL CARE, AMERICAN SOCIETY OFHEALTH-SYSTEM PHARMACISTS, 2007 and Rational Design of OralModified-release Drug Delivery Systems at page 469 in DEVELOPING SOLIDORAL DOSAGE FORMS: PHARMACEUTICAL THEORY AND PRACTICE, Academic Press,Elsevier, 2009. As used herein, “modified release formulation” or“modified release portion” in one embodiment refers to a compositionthat releases its gamma-hydroxybutyrate according a multiphase deliverythat is comprised in the fourth class of MR products, e.g. delayedextended release. As such it differs from the delayed release productsthat are classified in the first class of MR products.

As used herein the terms “coating”, “coating layer,” “coating film,”“film coating” and like terms are interchangeable and have the samemeaning. The terms refer to the coating applied to a particle comprisingthe gamma-hydroxybutyrate that controls the modified release of thegamma-hydroxybutyrate.

As used herein, “meal state” or “meal mode” includes the fed state, 2hours post meal, and the fasted mode. A “fed state” or “fed mode”includes the period of time immediately after consumption of a meal upto two hours post meal. The fed state may include the period less thantwo hours after eating. A “fasted state” or “fasted mode” includes theperiod of time after 8 hours post meal consumption. “2 hours post meal”includes the period of time between the fed state and the fasted state.For example, “2 hours post meal” may include the period between at least2 hours and 8 hours post meal. In all pharmacokinetic testing describedherein, unless otherwise stated, the dosage form, or the initial dosageform if the dosing regimen calls for more than one administration, isadministered less than two hours after eating, approximately two hoursafter eating, or more than 8 hours after eating. For example, the dosageform may be administered less than two hours after consumption of astandardized dinner, approximately two hours after consumption of astandardized dinner, or more than 8 hours after consumption of astandardized dinner. The standardized dinner may consist of 25.5% fat,19.6% protein, and 54.9% carbohydrates.

A “similar PK profile”, a “substantially similar PK profile”, or“comparable bioavailability” means that the mean AUC_(inf) of a testproduct is from 80% to 125% of the mean AUC_(inf) of a reference productin a suitably designed cross-over trial, the mean plasma concentrationat 8 hours (C_(8h)) of the test product is from 40% to 130% of the meanplasma concentration at 8 hours (C_(8h)) of the reference product,and/or that the maximum plasma concentration (C_(max)) of the testproduct is from 50% to 140% of the C_(max) of the reference product.

As used herein, “dose proportional” occurs when increases in theadministered dose are accompanied by proportional increases in the PKprofile, such as the AUC or C_(max).

A “fed state PK profile” means the mean AUC_(inf), the mean plasmaconcentration at 8 hours (C_(8h)), and/or the maximum plasmaconcentration (C_(max)) of the composition when administered less thantwo hours after eating.

A “2 hour post meal administration PK profile” means the mean AUC_(inf),the mean plasma concentration at 8 hours (C_(8h)), and/or the maximumplasma concentration (C_(max)) of the composition when administered atleast two hours after eating.

Type 1 Narcolepsy (NT1) refers to narcolepsy characterized by excessivedaytime sleepiness (“EDS”) and cataplexy. Type 2 Narcolepsy (NT2) refersto narcolepsy characterized by excessive daytime sleepiness withoutcataplexy. A diagnosis of narcolepsy (with or without cataplexy) may beconfirmed by one or a combination of (i) an overnight polysomnogram(PSG) and a Multiple Sleep Latency Test (MSLT) performed within the last2 years, (ii) a full documentary evidence confirming diagnosis from thePSG and MSLT from a sleep laboratory must be made available, (iii)current symptoms of narcolepsy including: current complaint of EDS forthe last 3 months (ESS greater than 10), (iv) mean MWT less than 8minutes, (v) mean number of cataplexy events of 8 per week on baselineSleep/Cataplexy Diary, and/or (vi) presence of cataplexy for the last 3months and 28 events per week during screening period.

As used herein, “adverse events” (AEs) or “treatment emergent adverseevents” (TEAEs) means self-reported adverse events by a patientadministered a composition for which the AEs are related. AEs or TEAEsmay include but not limited to gastrointestinal disorders, nervoussystem disorders, somnolence, dizziness, nausea, headache, feelingdrunk, vomiting, and/or fatigue.

Unless otherwise specified herein, percentages, ratios and numericvalues recited herein are based on weight; averages and means arearithmetic means; all pharmacokinetic measurements based on themeasurement of bodily fluids are based on plasma concentrations.

It will be understood, when defining a composition by itspharmacokinetic or dissolution properties herein, that the formulationcan in the alternative be defined as “means for” achieving the recitedpharmacokinetic or dissolution properties. Thus, a formulation in whichthe modified release portion releases less than 20% of itsgamma-hydroxybutyrate at one hour can instead be defined as aformulation comprising “means for” or “modified release means for”releasing less than 20% of its gamma-hydroxybutyrate at one hour. Itwill be further understood that the structures for achieving the recitedpharmacokinetic or dissolution properties are the structures describedin the examples hereof that accomplish the recited pharmacokinetic ordissolution properties.

Oral Pharmaceutical Composition for Administration Less than Two Hoursafter Eating

As the prior art demonstrates, it is extremely difficult to find aformulation that may be administered less than 2 hours after eating ameal and that has pharmacokinetic properties comparable to an immediaterelease liquid solution of sodium oxybate administered twice nightlytaken at least 2 hours after eating.

The inventors have discovered a novel relationship between in vivogamma-hydroxybutyrate absorption of modified release particles and theeffect of food on the absorption of gamma-hydroxybutyrate which permits,for the first time, a composition of gamma-hydroxybutyrate that may beadministered less than 2 hours after eating that approximates thebioavailability of a twice-nightly equipotent immediate release liquidsolution of sodium oxybate administered at least 2 hours after eating,and that does so across a range of therapeutic doses.

Provided herein is an oral pharmaceutical composition for the treatmentof narcolepsy, cataplexy, or excessive daytime sleepiness that includesgamma-hydroxybutyrate in a unit dose suitable for administration lessthan two hours after eating. In various embodiments, the composition mayinclude gamma-hydroxybutyrate in an extended release formulation,delayed release formulation, or modified release formulation.

Surprisingly, the composition may be administered at any time aftereating without being significantly impacted by a food effect. In anembodiment, the composition may be administered less than two hoursafter eating. For example, the composition may be administeredconcurrently with food or may be administered immediately after eating,at least 15 minutes after eating, at least 30 minutes after eating, atleast 1 hour after eating, at least 1.5 hours after eating, or less than2 hours after eating.

The composition may provide a substantially similar fed state PK profileand 2 hour post meal administration PK profile. For example, theAUC_(inf) for the composition administered less than two hours aftereating may be substantially similar to the AUC_(inf) when the samecomposition is administered at least two hours after eating. In anotherexample, the C_(max) for the composition administered less than twohours after eating may be substantially similar to the C_(max) when thesame composition is administered at least two hours after eating.

In an embodiment, when the composition is administered less than twohours after eating, it may achieve a mean AUC_(inf) that isbioequivalent to the mean AUC_(inf) provided by an equal dose of thecomposition administered at least two hours after eating. In someembodiments, when the composition is administered less than two hoursafter eating, it may achieve a mean AUC_(inf) that is from 50% to 120%,from 60% to 120%, from 70% to 120%, from 75% to 100%, from 80% to 100%,from 80 to 100%, from 90% to 100%, from 50% to 95%, or from 60% to 90%of the mean AUC_(inf) provided by an equal dose of the compositionadministered at least two hours after eating.

In an embodiment, when the composition is administered less than twohours after eating, it may achieve a mean C_(max) that is bioequivalentto the mean C_(max) provided by an equal dose of the compositionadministered at least two hours after eating. In some embodiments, whenthe composition is administered less than two hours after eating, it mayachieve a mean C_(max) that is from 50% to 140%, from 60% to 120%, from70% to 120%, from 75% to 100%, from 80% to 100%, from 80 to 100%, from90% to 100%, from 50% to 95%, or from 60% to 90% of the mean C_(max)provided by an equal dose of the composition administered at least twohours after eating.

The composition may provide a substantially similar fed state PK profileand fasted state PK profile. In an example, the AUC_(inf) for thecomposition administered less than two hours after eating may besubstantially similar to the AUC_(inf) when the same composition isadministered in the fasted state. In yet another example, the C_(max)for the composition administered less than two hours after eating may besubstantially similar to the C_(max) when the same composition isadministered in the fasted state.

In an embodiment, when the composition is administered less than twohours after eating, it may achieve a mean AUC_(inf) that isbioequivalent to the mean AUC_(inf) provided by an equal dose of thecomposition administered in the fasted state. In some embodiments, whenthe composition is administered less than two hours after eating, it mayachieve a mean AUC_(inf) that is from 50% to 120%, from 60% to 120%,from 70% to 120%, from 75% to 100%, from 80% to 100%, from 80 to 100%,from 90% to 100%, from 50% to 95%, or from 60% to 90% of the meanAUC_(inf) provided by an equal dose of the composition administered inthe fasted state. In an embodiment, when the composition is administeredless than two hours after eating, it may achieve a mean AUC_(inf) with a90% Cl that fall within the 80-125% bioequivalence range of an equaldose of the composition administered in the fasted state with no effectboundaries. In some examples, the composition provides a mean AUC_(inf)when administered less than two hour after eating that is 80%-95% of themean AUC_(inf) when the composition is administered while fasting. Inadditional examples, the composition provides a mean AUC_(inf) whenadministered less than two hour after eating that is 85%-90% of the meanAUC_(inf) when the composition is administered while fasting. In atleast one example, a ratio of the AUC_(last) (fed) to AUC_(last)(fasted) may be about 86 with a 90% Cl of 79.9-92.6. In at least oneexample, a ratio of the AUC_(inf) (fed) to AUC_(inf) (fasted) may beabout 86.1 with a 90% Cl of 80.0-92.7.

In an embodiment, when the composition is administered less than twohours after eating, it may achieve a mean C_(max) that is bioequivalentto the mean C_(max) provided by an equal dose of the compositionadministered in the fasted state. In some embodiments, when thecomposition is administered less than two hours after eating, it mayachieve a mean C_(max) that is from 50% to 140%, from 60% to 120%, from70% to 120%, from 75% to 100%, from 80% to 100%, from 80 to 100%, from90% to 100%, from 50% to 95%, or from 60% to 90% of the mean C_(max)provided by an equal dose of the composition administered in the fastedstate. In an embodiment, when the composition is administered less thantwo hours after eating, it may achieve a mean C_(max) with a 90% Cl thatfall within the 80-125% bioequivalence range of an equal dose of thecomposition administered in the fasted state with no effect boundaries.In some examples, the composition provides a mean C_(max) whenadministered less than two hours after eating that is 55%-80% of themean C_(max) when the composition is administered while fasting. Inadditional examples, the composition provides a mean C_(max) whenadministered less than two hours after eating that is 60%-75% of themean C_(max) when the composition is administered while fasting. In atleast one example, a ratio of the C_(max) (fed) to C_(max) (fasted) maybe about 66.6 with a 90% Cl of 58.2-76.5.

In an embodiment, the composition provides a C_(max) that is doseproportional. In additional embodiments, the composition provides nodose dumping.

In an embodiment, compositions of gamma-hydroxybutyrate administeredless than two hours after eating may optimize the bioavailability of thegamma-hydroxybutyrate, and roughly approximate the bioavailability of anequal dose of an immediate release liquid solution of sodium oxybateadministered twice nightly where the first dose is administered at leasttwo hours after eating.

In some embodiments, the compositions of gamma-hydroxybutyrateadministered less than two hours after eating may roughly approximate orexceed the bioavailability of an equal dose of an immediate releasesolution of sodium oxybate administered twice nightly at least two hoursafter eating, across the entire therapeutic range of sodium oxybatedoses.

In other embodiments, the compositions of gamma-hydroxybutyrateadministered less than two hours after eating may produce very littleresidual drug content in the bloodstream of most patients up to 8 hoursafter administration but may still be similar to the one observed afteradministration of an equal dose of an immediate release liquid solutionof sodium oxybate administered twice nightly at least two hours aftereating.

In an embodiment, there is no significant reduction in safety orefficacy to a patient following administration of the composition. Inanother embodiment, the compositions of gamma-hydroxybutyrate mayimprove the therapeutic effectiveness and safety profile ofgamma-hydroxybutyrate when administered less than two hours after eatingbased on novel pharmacokinetic profiles. For example, administration ofthe gamma-hydroxybutyrate composition less than two hours after eatingmay result in fewer AEs than administration of the gamma-hydroxybutyratecomposition at least two hours after eating or in the fasted state.

In some embodiments, the gamma-hydroxybutyrate composition has a morefavorable safety profile as compared to an equal dose of immediaterelease liquid solution of sodium oxybate administered at t₀ and t_(4h)in equally divided doses. Most adverse events (AEs) may occur close toT_(max), during the C_(max) period. In an example, thegamma-hydroxybutyrate composition may have only one T_(max) and oneC_(max) per day due to the once daily administration as compared tomultiple T_(max) and C_(max) in an immediate release formulation (suchas Xyrem®) requiring multiple administrations per day. Therefore, havingonly one T_(max) and one C_(max) by administration of thegamma-hydroxybutyrate composition may result in fewer AEs thanadministration of the immediate release formulation. In an additionalexample, the C_(max) of the gamma-hydroxybutyrate composition may bebetween the C_(max) of the first peak and the C_(max) of the second peakof Xyrem®. The gamma-hydroxybutyrate composition may have a lowerC_(max) than the C_(max) of an equal dose of an immediate releaseformulation, such that administration of the gamma-hydroxybutyratecomposition may result in fewer AEs than administration of the immediaterelease formulation. Therefore, administration of thegamma-hydroxybutyrate composition once daily may result in fewer AEsthan administration of an equal dose of immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses. In other embodiments, the onset of efficacy of thecomposition may be earlier than Xyrem® in the fed state.

The gamma-hydroxybutyrate composition may offer a substantialimprovement in safety profile to narcolepsy, cataplexy, or excessivedaytime sleepiness patients by reducing the amount of adverse events(AEs) over an 8 hour, 12 hour, 16 hour, 20 hour, 24 hour, and/or 48 hourtime period following administration of the gamma-hydroxybutyratecomposition, as compared to an immediate release sodium oxybate (e.g.,Xyrem®) formulation. In particular, the gamma-hydroxybutyratecomposition may result in fewer adverse events and fewer C_(max) periodsover an 8 hour, 12 hour, 16 hour, 20 hour, 24 hour, and 48 hour timeperiod, as compared to an immediate release sodium oxybate (e.g.,Xyrem®) formulation. Since it appears AEs may be closely related toC_(max), by virtue of the gamma-hydroxybutyrate composition having fewerC_(max) periods than Xyrem®, the gamma-hydroxybutyrate composition mayalso have fewer AEs over an 8 hour, 12 hour, 16 hour, 20 hour, 24 hour,and/or 48 hour time period, as compared to an immediate release sodiumoxybate (e.g., Xyrem®) formulation. Thus, the gamma-hydroxybutyratecomposition may have a superior safety profile and/or reduced AEscompared to the prior art (e.g., Xyrem®) or any sodium oxybatecomposition requiring administration more frequently than once-daily.

In yet another embodiment, the compositions of gamma-hydroxybutyrateadministered less than two hours after eating may yield a similarpharmacokinetic profile compared to an immediate release liquid solutionof sodium oxybate administered twice nightly at least two hours aftereating while potentially giving a reduced dose.

In another embodiment, the compositions of gamma-hydroxybutyrate mayallow administration less than two hours after eating compared to thecommercial treatment Xyrem®.

In other embodiments, the compositions of gamma-hydroxybutyrate may beadministered less than two hours after eating, or may be administered inthe fed or fasted state, with improved dissolution and pharmacokineticprofiles compared to an immediate release liquid solution of sodiumoxybate administered twice nightly at least two hours after eating.

In an embodiment, the composition provides an AUC_(inf) bioequivalent toan AUC_(inf) of Xyrem® as depicted in FIG. 4A, 5A, 5B, 6A, 6B, 7A, or7B. In another embodiment, the composition provides a C_(max) that isless than the second C_(max) of Xyrem® as depicted in FIG. 4A, 5A, 5B,6A, 6B, 7A, or 7B. In one embodiment, the C_(max) of the compositionwhen administered less than two hours after eating may be between thefirst and second C_(max) of Xyrem®. In yet another embodiment, thecomposition provides a C_(max) that is substantially less than theC_(max) of Xyrem® as depicted in FIG. 4A, 5A, 5B, 6A, 6B, 7A, or 7B. Thecomposition may provide a C_(max) that is 10-60% less than the C_(max)of Xyrem® as depicted in FIG. 4A, 5A, 5B, 6A, 6B, 7A, or 7B. Thecomposition may provide a change in C_(max) between when the compositionis administered at least two hours after eating and when the compositionis administered less than two hours after eating that is 10-60% lessthan the change in C_(max) of Xyrem as depicted in a figure selectedfrom the group consisting of FIGS. 4A, 5A, 5B, 6A, 6B, 7A, and 7B. Thecomposition may provide an AUC that is more dose proportional than theAUC of Xyrem® as depicted in FIG. 4A, 5A, 5B, 6A, 6B, 7A, or 7B.

In particular, a 6 g dose of a composition of gamma-hydroxybutyrateadministered less than two hours after eating has been shown to achievea mean AUC_(inf) of greater than 230 hr*μg/mL, and a mean C_(max) thatis from 50% to 140% of the mean C_(max) provided by an equal dose ofimmediate release liquid solution of sodium oxybate administered at t₀and t_(4h) in equally divided doses, where the first dose isadministered at least two hours after eating a standardized meal. Forexample, a 6 g dose of the composition administered less than two hoursafter eating may have a mean AUC_(inf) of about 242 hr*μg/mL and a meanC_(max) of about 64 μg/mL. In addition, a 9 g dose of a composition ofgamma-hydroxybutyrate administered less than two hours after eating mayachieve a mean AUC_(inf) of greater than 400 hr*μg/mL, and a meanC_(max) that may be from 50% to 140% of the mean C_(max) provided by anequal dose of immediate release liquid solution of sodium oxybateadministered at t₀ and t_(4h) in equally divided doses where the firstdoes is administered at least two hours after a standardized meal. Thismay be seen by comparing the release profiles and pharmacokineticprofiles in Examples 1-7.

The compositions of gamma-hydroxybutyrate may have both immediaterelease and modified release portions. The release ofgamma-hydroxybutyrate from the immediate release portion is practicallyuninhibited, and occurs almost immediately in 0.1N hydrochloric aciddissolution medium. In contrast, while the modified release portion alsomay release its gamma-hydroxybutyrate almost immediately when fullytriggered, the release is not triggered until a predetermined lag-timeor the drug is subjected to a suitable dissolution medium such as aphosphate buffer pH 6.8 dissolution medium. Without wishing to be boundby any theory, it is believed that food may have no or low impact on themodified release portion of the composition, as thegamma-hydroxybutyrate from the modified release portion is absorbed inthe latter part of the gastro-intestinal tract.

Formulations that achieve this improved bioavailability in the fed statemay be described using several different pharmacokinetic parameters. Anembodiment of the composition of gamma-hydroxybutyrate includesimmediate release and modified release portions, where a 6 g dose of theformulation, when administered less than two hours after eating, mayachieve a mean AUC_(inf) of greater than 230, 240, 245, 300, 325, 340,375, 400, 425, or 450 hr*microgram/mL. In an embodiment, a 6 g does ofthe composition has a mean AUC_(inf) of greater than 230hr*microgram/mL. In an embodiment, a 6 g does of the composition has amean AUC_(inf) of about 242 hr*microgram/mL. For example, when thecomposition is administered less than two hours after eating, itachieves a mean AUC_(inf) that is from 50% to 120%, from 60% to 120%,from 70% to 120%, from 75% to 100%, from 80% to 100%, from 80 to 100%,from 90% to 100%, from 50% to 95%, or from 60% to 90% of the meanAUC_(inf) provided by an equal dose of the composition administered atleast two hours after eating.

An embodiment of the composition of gamma-hydroxybutyrate includesimmediate release and modified release portions, where a 6 g dose of theformulation, when administered less than two hours after eating, mayachieve a mean C_(max) of greater than 55, 60, 65, or 70 μg/mL. Forexample, a 6 g dose of the composition has a mean C_(max) of about 64μg/mL. An embodiment of the composition of gamma-hydroxybutyrateincludes immediate release and modified release portions, where a 6 gdose of the formulation, when administered less than two hours aftereating, may achieve a mean C_(max) that is from 50% to 140%, from 60% to140%, from 70% to 140%, from 75% to 135%, from 80% to 135%, from 80 to130%, from 90% to 110%, from 50% to 95%, or from 60% to 90% of the meanC_(max) provided by an equal dose of an immediate release liquidsolution of sodium oxybate (e.g. Xyrem®) administered at t₀ and t_(4h)in equally divided doses approximately two hours after a standardizedmeal. In one embodiment, a 6 g dose of the composition has a meanC_(max) from 60% to 90%, or from 60% to 140% of the mean C_(max)provided by an equal dose of an immediate release liquid solution ofsodium oxybate (e.g. Xyrem®) administered at t₀ and t_(4h) in equallydivided doses approximately two hours after a standardized meal. Inother embodiments, the mean C_(max) is from 100% to 150% of the of themean C_(max) of a first peak of the equal dose of immediate releaseliquid solution of sodium oxybate administered at t₀ and t_(4h) inequally divided doses at least two hours after eating and the meanC_(max) is from 80% to 100% of the of the mean C_(max) of a second peakof the equal dose of immediate release liquid solution of sodium oxybateadministered at t₀ and t_(4h) in equally divided doses at least twohours after eating.

An embodiment of the composition of gamma-hydroxybutyrate includesimmediate release and modified release portions, where a 9 g dose of theformulation, when administered less than two hours after eating, mayachieve a mean AUC_(inf) of greater than 350, 400, 450, 500, 525, or 550hr*microgram/mL. In one embodiment, a 9 g dose of the composition mayhave a mean AUC_(inf) of greater than 400 hr*microgram/mL.

An embodiment of the composition of gamma-hydroxybutyrate includesimmediate release and modified release portions, where a 9 g dose of theformulation, when administered less than 2 hours after eating, may havea mean C_(max) that is from 50% to 140%, from 60% to 140%, from 70% to140%, from 75% to 135%, from 80% to 135%, from 80 to 130%, from 90% to110%, from 50% to 95%, or from 60% to 90% of the mean C_(max) providedby an equal dose of an immediate release liquid solution of sodiumoxybate (e.g. Xyrem®) administered at t₀ and t_(4h) in equally divideddoses approximately two hours after a standardized meal. In oneembodiment, a 9 g dose of the composition may have a mean C_(max) from60% to 90% or 60% to 120% of the mean C_(max) provided by an equal doseof an immediate release liquid solution of sodium oxybate (e.g. Xyrem®)administered at t₀ and t_(4h) in equally divided doses approximately twohours after a standardized meal.

An embodiment of the composition of gamma-hydroxybutyrate yields aplasma concentration versus time curve when administered at a strengthof 6 g less than two hours after a standardized evening mealsubstantially as depicted in FIG. 2A.

Another embodiment of the composition of gamma-hydroxybutyrate yields aplasma concentration versus time curve when administered once nightly ata strength of 6 g less than two hours after eating substantially asdepicted in FIG. 4B.

Yet another embodiment of the composition of gamma-hydroxybutyrateyields a plasma concentration versus time curve when administered oncenightly at a strength of 6 g less than two hours after eatingsubstantially as depicted in FIG. 5A.

An embodiment of the composition of gamma-hydroxybutyrate yields aplasma concentration versus time curve when administered once nightly ata strength of 9 g less than two hours after eating substantially asdepicted in FIG. 6A.

Another embodiment of the composition of gamma-hydroxybutyrate yields anAUC profile when administered once nightly at a strength of 6 g between0 and 4 hours after eating substantially as depicted in FIG. 7A.

Yet another embodiment of the composition of gamma-hydroxybutyrateyields a C_(max) profile when administered once nightly at a strength of6 g between 0 and 4 hours after a standardized evening mealsubstantially as depicted in FIG. 7B.

In any of these embodiments, the formulation may be effective to treatnarcolepsy Type 1 or Type 2. The treatment of narcolepsy is defined asreducing excessive daytime sleepiness or reducing the frequency ofcataplectic attacks. In various embodiments, the composition issufficient to be administered once daily. For example, the compositionmay be sufficient to administer in the morning or at night less than 2hours after eating a meal. The formulation is also effective to inducesleep for at least 6 to 8 consecutive hours. In one embodiment, thecomposition administered less than two hours after eating is effectiveto induce sleep for at least 8 consecutive hours. In variousembodiments, the formulation is effective to induce sleep for at least 6hours, at least 7 hours, at least 8 hours, at least 9 hours, or at least10 hours. In other embodiments, the formulation is effective to inducesleep for up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, orup to 10 hours.

In any of these embodiments, the composition may include immediaterelease and modified release portions, where the modified releaseportion includes gamma hydroxybutyrate particles coated by a polymercarrying free carboxylic groups and a hydrophobic compound having amelting point equal or greater than 40° C., and the ratio ofgamma-hydroxybutyrate in the immediate release portion and the modifiedrelease portion is from 10/90 to 65/35. The polymers comprising freecarboxylic groups may have a pH dissolution trigger of from 5.5 to 6.97and may be methacrylic acid copolymers having a pH dissolution triggerof from 5.5 to 6.97.

Structural Embodiments

Various techniques are known for formulating modified release dosageforms including, for example, the techniques described in U.S. Pat. No.8,101,209 to Legrand et al. (“Legrand”). Legrand provides a systemensuring that the active ingredient is released with certainty from themodified release dosage form by means of a dual mechanism of“time-dependent” and “pH-dependent” release. Legrand did not describeany dosage forms for delivering sodium oxybate or other forms ofgamma-hydroxybutyrate administered less than two hours after eating.

In various embodiments, the composition of any of the embodiments hereinmay be administered at any meal state. In particular, the compositionmay be administered in the fed state, at least two hours after eating,or in the fasted state. In one embodiment, the composition isadministered in the fed state, which is less than two hours aftereating. For example, the composition may be administered while eating,immediately after eating, up to 30 minutes after eating, at least 30minutes after eating, up to 45 minutes after eating, up to 1 hour aftereating, up to 1.25 hours after eating, up to 1.5 hours after eating, upto 1.75 hours after eating, up to 1.8 hours after eating, up to 1.9hours after eating, or up to 1.95 hours after eating. In someembodiments, the composition may be administered less than two hoursafter eating a standardized evening meal.

In an embodiment, the composition of gamma-hydroxybutyrate may includeimmediate release and modified release portions, wherein: (a) themodified release portion comprises coated particles ofgamma-hydroxybutyrate; (b) the coating comprises a polymer carrying freecarboxylic groups and a hydrophobic compound having a melting pointequal or greater than 40° C.; and (c) the ratio of gamma-hydroxybutyratein the immediate release portion and the modified release portion isfrom 10/90 to 65/35.

In an embodiment, the composition of gamma-hydroxybutyrate may includeimmediate release and modified release portions, a suspending orviscosifying agent, and an acidifying agent, wherein: (a) the modifiedrelease portion comprises coated particles of gamma-hydroxybutyrate; (b)the coating comprises a polymer carrying free carboxylic groups and ahydrophobic compound having a melting point equal or greater than 40°C.; and (c) the ratio of gamma-hydroxybutyrate in the immediate releaseportion and the modified release portion is from 10/90 to 65/35.

In an embodiment, the composition of gamma-hydroxybutyrate may includeimmediate release and modified release portions, wherein: (a) themodified release portion comprises coated particles ofgamma-hydroxybutyrate; (b) the coating comprises a polymer carrying freecarboxylic groups and a hydrophobic compound having a melting pointequal or greater than 40° C.; (c) the weight ratio of the hydrophobiccompound to the polymer carrying free carboxylic groups is from 0.4 to4; (d) the ratio of gamma-hydroxybutyrate in the immediate releaseportion and the modified release portion is from 10/90 to 65/35; and (e)the coating is from 10 to 50% of the weight of the particles.

In an embodiment, the composition of gamma-hydroxybutyrate may includeimmediate release and modified release portions, wherein: (a) themodified release portion comprises coated particles ofgamma-hydroxybutyrate; (b) the coating comprises a polymer carrying freecarboxylic groups having a pH trigger of from 5.5 to 6.97 and ahydrophobic compound having a melting point equal or greater than 40°C.; (c) the weight ratio of the hydrophobic compound to the polymercarrying free carboxylic groups is from 0.4 to 4; (d) the ratio ofgamma-hydroxybutyrate in the immediate release portion and the modifiedrelease portion is from 10/90 to 65/35; and (e) the coating is from 10to 50% of the weight of the particles.

In an embodiment, the composition of gamma-hydroxybutyrate may includeimmediate release and modified release portions, wherein: (a) themodified release portion comprises coated particles ofgamma-hydroxybutyrate; (b) the coating comprises a methacrylic acidcopolymer carrying free carboxylic groups having a pH trigger of from5.5 to 6.97 and a hydrophobic compound having a melting point equal orgreater than 40° C.; (c) the weight ratio of the hydrophobic compound tothe polymer carrying free carboxylic groups is from 0.4 to 4; (d) theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 10/90 to 65/35; and (e) the coating isfrom 10 to 50% of the weight of the particles.

In various embodiments, gamma-hydroxybutyrate may be present in thecomposition as a 4.5 g, 6.0 g, 7.5 g, or 9.0 g dose. In someembodiments, the dosage of gamma-hydroxybutyrate may be sufficient toadminister the composition once daily.

Pharmacokinetics

As mentioned in the definitions section of this document, each of thesub-embodiments may be used to further characterize and limit each ofthe foregoing principal embodiments. In addition, more than one of thefollowing sub-embodiments may be combined and used to furthercharacterize and limit each of the foregoing principal embodiments, inany manner that is mathematically and physically possible.

In an embodiment, the oral pharmaceutical composition ofgamma-hydroxybutyrate may be in a unit dose suitable for administrationless than two hours after eating for the treatment of narcolepsy,cataplexy, or excessive daytime sleepiness. Without being limited to aparticular theory, the composition may include a modified releaseportion that delays release of a portion of the gamma-hydroxybutyrateuntil the composition reaches the small intestine, such that ingestionof food has a limited effect on the absorption of thegamma-hydroxybutyrate.

In an embodiment, the oral pharmaceutical composition ofgamma-hydroxybutyrate may be in a unit dose suitable for administrationonce daily for the treatment of narcolepsy, cataplexy, or excessivedaytime sleepiness. In an example, the composition may exhibit rapidinitial absorption comparable to twice-nightly IR sodium oxybate. Inanother example, the composition may demonstrate a lower overall C_(max)than twice-nightly IR sodium oxybate. In other examples, the compositionmay provide mean blood concentrations (ug/ml) at 8 hours similar to thatof twice-nightly IR sodium oxybate.

In various embodiments, the composition provides a substantially similarfed state PK profile and 2 hour post meal administration PK profile. Insome embodiments, a 4.5 g, 7.5 g, and/or 9 g dose may exhibit a PKprofile consistent with those desired for once-nightly dosing. Invarious embodiments, the composition exhibits pharmacokinetics that aredose proportional when administered once daily, 2 hours post meal. In anembodiment, the composition provides a C_(max) that is doseproportional. For example, the composition provides a C_(max) that isdose proportional across once daily doses of 4.5 g, 7.5 g, and 9 g. Inan embodiment, the composition provides an AUC that is doseproportional. For example, the C_(max) of a 6 g dose is proportional tothe C_(max) of a 9 g dose of the composition. In another embodiment, thecomposition is dose proportional by a factor of about 1 to about 1.3. Inan example, the C_(max) may be dose proportional by a factor of about 1.In another example, the AUC may be dose proportional by a factor ofabout 1.3. In some examples, the increase in the AUC may be slightlymore than proportional. The composition may exhibit predictableincreases in plasma levels with increasing doses, consistent with the PKprofile desired for a once-nightly sodium oxybate formulation.

In an embodiment, the once-nightly controlled-release sodium oxybatecomposition may demonstrate lower overall C_(max) and similar total AUC,compared to twice-nightly sodium oxybate. In an embodiment, theonce-nightly composition safety profile may be consistent with what isknown for sodium oxybate.

In an embodiment, the composition provides no dose dumping. For example,the ingestion of alcohol does not result in an immediate release ofgamma-hydroxybutyrate.

In another embodiment, there is no significant reduction in safety orefficacy to a patient following administration of the composition lessthan two hours after eating. In some embodiments, the safety is improvedover the administration of Xyrem®, such that the C_(max) of thecomposition is less than the C_(max) after administration of the seconddose of Xyrem® when administered in the fed state. In other embodiments,the composition is more effective than Xyrem® when administered in thefed state. For example, the C_(max) of the composition is higher thanthe C_(max) after administration of the first dose of Xyrem® whenadministered in the fed state.

In an embodiment, the composition provides an AUC_(inf) bioequivalent toan AUC_(inf) of Xyrem® as depicted in a figure selected from FIGS. 4A,5A, 5B, 6A, 6B, and 7A. In an embodiment, the composition provides aC_(max) that is less than the C_(max) of Xyrem® as depicted in a figureselected from FIGS. 4A, 5A, 5B, 6A, 6B, 7A, and 7B. In an embodiment,the composition provides a C_(max) that is substantially less than theC_(max) of Xyrem® as depicted in a figure selected from FIGS. 4A, 5A,5B, 6A, 6B, and 7B. In an embodiment, the composition provides a C_(max)that is 10-60% less than the C_(max) of Xyrem® as depicted in a figureselected from FIGS. 4A, 5A, 5B, 6A, 6B, and 7B. In an embodiment, thecomposition provides an AUC that is more dose proportional than the AUCof Xyrem® as depicted in a figure selected from FIGS. 4A, 5A, 5B, 6A,6B, and 7A.

In various embodiments, a 6 g dose of the composition ofgamma-hydroxybutyrate may be characterized as having been shown toachieve a mean AUC_(inf) of greater than 230, 240, 245, 250, 255, 260,275, 300, 325, or 350 hr*microgram/mL when administered once less thantwo hours after eating. An upper limit on mean AUC_(inf) for such 6 gdose may be set at 300 or 350 hr*μg/mL. In these embodiments, the 6 gdose of the composition may be administered less than two hours aftereating a meal. For example, the 6 g dose of the composition may beadministered once daily, in the morning or the evening. In otherembodiments, the 6 g dose of the composition may be administered in thefed state.

In additional embodiments, a 6 g dose of the composition ofgamma-hydroxybutyrate may be characterized as having been shown toachieve a mean C_(max) of greater than 50, 55, 60, 65, 70, 75, 80, 85,or 90 μg/mL when administered once less than two hours after eating. Anupper limit on mean C_(max) for such 6 g dose may be set at 75 or 90μg/mL. In these embodiments, the 6 g dose of the composition may beadministered less than two hours after eating a meal. For example, the 6g dose of the composition may be administered once daily, in the morningor the evening. In other embodiments, the 6 g dose of the compositionmay be administered in the fed state.

In additional embodiments, a 6 g dose of the composition ofgamma-hydroxybutyrate administered less than two hours after eating maybe characterized as having been shown to achieve a mean C_(max) that isfrom 50% to 140%, from 60% to 140%, from 70 to 140%, from 75% to 135%,from 80% to 135%, or from 80 to 130% of the mean C_(max) provided by anequal dose of immediate release liquid solution of gamma-hydroxybutyrateadministered at to and t₄ h in two equally divided doses administered atleast two hours after a standardized meal. In these embodiments, the 6 gdose of the composition may be administered less than two hours aftereating a meal. For example, the 6 g dose of the composition may beadministered once daily, in the morning or the evening. In otherembodiments, the 6 g dose of the composition may be administered in thefed state.

In various embodiments, a 6 g dose of the composition ofgamma-hydroxybutyrate may be characterized as having been shown toachieve a mean AUC_(8h) of greater than 1, 2, 3, 4, 5, or 6 μg/mL whenadministered once less than two hours after eating. An upper limit onmean AUC_(8h) for such 6 g dose may be set at 5 or 6 μg/mL. In theseembodiments, the 6 g dose of the composition may be administered lessthan two hours after eating a meal. For example, the 6 g dose of thecomposition may be administered once daily, in the morning or theevening. In other embodiments, the 6 g dose of the composition may beadministered in the fed state.

In various embodiments, a 6 g dose of the composition ofgamma-hydroxybutyrate may be characterized as having been shown toachieve a mean AUC₀₋₈ of greater than 150, 175, 200, 225, 250, 300, or350 hr*μg/mL when administered once less than two hours after eating. Anupper limit on mean AUC₀₋₈ for such 6 g dose may be set at 300 or 350hr*μg/mL. In these embodiments, the 6 g dose of the composition may beadministered less than two hours after eating a meal. For example, the 6g dose of the composition may be administered once daily, in the morningor the evening. In other embodiments, the 6 g dose of the compositionmay be administered in the fed state.

In various embodiments, a 6 g dose of the composition ofgamma-hydroxybutyrate may be characterized as having been shown toachieve a mean AUC_(0-t) of greater than 150, 175, 200, 225, 250, 300,or 350 hr*μg/mL when administered once less than two hours after eating.An upper limit on mean AUC_(0-t) for such 6 g dose may be set at 300 or350 hr*μg/mL. In these embodiments, the 6 g dose of the composition maybe administered less than two hours after eating a meal. For example,the 6 g dose of the composition may be administered once daily, in themorning or the evening. In other embodiments, the 6 g dose of thecomposition may be administered in the fed state.

In various embodiments, a 6 g dose of the composition ofgamma-hydroxybutyrate may be characterized as having been shown toachieve a mean % AUC, ext of greater than 0.1%, 0.2%, or 0.3% whenadministered once less than two hours after eating. In theseembodiments, the 6 g dose of the composition may be administered lessthan two hours after eating a meal. For example, the 6 g dose of thecomposition may be administered once daily, in the morning or theevening. In other embodiments, the 6 g dose of the composition may beadministered in the fed state.

In various embodiments, a 6 g dose of the composition ofgamma-hydroxybutyrate may be characterized as having been shown toachieve a t_(max) of greater than 0.5, 1, 1.5, 2, or 2.5 hours whenadministered once less than two hours after eating. In theseembodiments, the 6 g dose of the composition may be administered lessthan two hours after eating a meal. For example, the 6 g dose of thecomposition may be administered once daily, in the morning or theevening. In other embodiments, the 6 g dose of the composition may beadministered in the fed state.

In various embodiments, a 6 g dose of the composition ofgamma-hydroxybutyrate may be characterized as having been shown toachieve a mean t of greater than 0.5, 1, or 1.5 hours when administeredonce less than two hours after eating. In these embodiments, the 6 gdose of the composition may be administered less than two hours aftereating a meal. For example, the 6 g dose of the composition may beadministered once daily, in the morning or the evening. In otherembodiments, the 6 g dose of the composition may be administered in thefed state.

In one embodiment, a 6 g dose of the composition administered less thantwo hours after eating may achieve a mean AUC_(inf) of greater than 230hr·μg/mL, and a mean C_(max) that is from 50% to 140% of the meanC_(max) provided by an equal dose of immediate release liquid solutionof sodium oxybate administered at t₀ and t_(4h) in equally divided dosesat least two hours after eating.

In various embodiments, a 9 g dose of the composition ofgamma-hydroxybutyrate administered less than two hours after eating maybe characterized as having been shown to achieve a mean AUC_(inf) ofgreater than 350, 400, 450, 460, 470, 480, 490, 500, 525, 550, 575, or600 hr*μg/mL. An upper limit on mean AUC_(inf) for such 9 g dose may beset at 550 or 600 hr*microgram/mL. In these embodiments, the 9 g dose ofthe composition may be administered less than two hours after eating ameal. For example, the 9 g dose of the composition may be administeredonce daily, in the morning or the evening. In other embodiments, the 9 gdose of the composition may be administered in the fed state.

In additional embodiments, a 9 g dose of the composition ofgamma-hydroxybutyrate administered less than two hours after eating maybe characterized as having a mean C_(max) of greater than 60, 65, 70,75, 80, 85, 90, 95, or 100 μg/mL. An upper limit on mean C_(max) forsuch 9 g dose may be set at 125 or 100 μg/mL. In these embodiments, the9 g dose of the composition may be administered less than two hoursafter eating a meal. For example, the 9 g dose of the composition may beadministered once daily, in the morning or the evening. In otherembodiments, the 9 g dose of the composition may be administered in thefed state.

In additional embodiments, a 9 g dose of the composition ofgamma-hydroxybutyrate administered less than two hours after eating maybe characterized as having a mean C_(max) that is from 50% to 120% orfrom 60% to 120% of the mean C_(max) provided by an equal dose ofimmediate release liquid solution of gamma-hydroxybutyrate administeredat t₀ and t_(4h) in two equally divided doses administered at least twohours after a standardized meal. In these embodiments, the 9 g dose ofthe composition may be administered less than two hours after eating ameal. For example, the 9 g dose of the composition may be administeredonce daily, in the morning or the evening. In other embodiments, the 9 gdose of the composition may be administered in the fed state.

In one embodiment, a 9 g dose of the composition administered less thantwo hours after eating may achieve a mean AUC_(inf) of greater than 500hr·μg/mL, and a mean C_(max) that is from 50% to 120% of the meanC_(max) provided by an equal dose of immediate release liquid solutionof sodium oxybate administered at t₀ and t_(4h) in equally divided dosesat least two hours after a standardized evening meal.

Still further embodiments may be defined based on a pharmacokineticcomparison of the composition of gamma-hydroxybutyrate to an immediaterelease solution of gamma-hydroxybutyrate. Therefore, in additionalembodiments, the composition of gamma-hydroxybutyrate administered lessthan two hours after eating may achieve a relative bioavailability (RBA)of greater than 80%, 85%, 90%, or 95% when compared to an equal dose ofan immediate release liquid solution of sodium oxybate administered att₀ and t_(4h) in equally divided doses administered at least two hoursafter a standardized meal. For example, a 6 g and 9 g dose of theformulation administered less than two hours after eating may have anRBA of greater than 80%, 85% or 90% when compared to an equal dose of animmediate release liquid solution of sodium oxybate administered at t₀and t_(4h) in equally divided doses administered at least two hoursafter a standardized meal

The compositions of gamma-hydroxybutyrate may also be defined by theconcentration/time curves that they produce when tested according to theExamples. Therefore, in other embodiments, a 6 g or 9 g dose of thecomposition of gamma-hydroxybutyrate administered less than two hoursafter eating may achieve a time/concentration curve substantially asshown in FIGS. 5A and 6A respectively herein. In other embodiments, thecomposition may achieve a time/concentration curve substantially asshown in FIG. 2A, 3B, or 4B herein.

The compositions of gamma-hydroxybutyrate may also be defined based onthe time required to reach maximum blood concentration ofgamma-hydroxybutyrate. Thus, in additional embodiments, the compositionof gamma-hydroxybutyrate may achieve a mean T_(max) of 0.5 to 2.5 hours.In various embodiments, the composition of gamma-hydroxybutyrate mayachieve a mean T_(max) of about 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0,2.25, or 2.5 hours when administered less than two hours after eating. Alower limit on the median T_(max) in any of the foregoing ranges canalternatively be set at 0.5 or 1.0 hours.

In another embodiment, a 6 g dose of the composition may achieve a meanAUC_(inf) of greater than 230 hr·μg/mL and a mean C_(max) of greaterthan 60 microgram/mL when administered less than two hours after eating.

In still another embodiment, a 9 g dose of the formulation may achieve amean AUC_(inf) of greater than 400 hr·μg/mL and a mean C_(max) ofgreater than 60 microgram/mL when administered less than two hours aftereating.

In an embodiment, 4.5 g, 7.5 g and 9 g doses of the composition mayexhibit similar overall mean pharmacokinetics profiles when administeredonce daily, 2 hours after eating. In some embodiments, 4.5 g, 7.5 g and9 g doses of the composition may exhibit mean pharmacokinetics profilesas shown in FIG. 8 when administered once daily, 2 hours after eating.In an example, 4.5 g, 7.5 g and 9 g doses of the composition may exhibita median T_(max) between 1.5 and 2 hours (FIG. 8). In an example, 4.5 g,7.5 g and 9 g doses of the composition may achieve a mean C_(max) from42.9 to 84.5 μg/mL across the increasing doses. Following C_(max), bloodlevels may gradually decrease overnight. In an example, the compositionmay achieve a mean AUC_(inf) of 191, 358 and 443 μg·h/mL for the 4.5,7.5 and 9 g doses respectively when administered once daily, 2 hoursafter eating. In an example, the composition may exhibit meanconcentrations at 8 hours of 4.8, 19.7 and 25.5 μg/mL for the 4.5, 7.5and 9 g doses respectively when administered once daily, 2 hours aftereating.

Structural Embodiments

The compositions of gamma-hydroxybutyrate may be provided in any dosageform that is suitable for oral administration, including tablets,capsules, liquids, orally dissolving tablets, and the like. In oneembodiment, they are provided as dry particulate formulations (i.e.granules, powders, coated particles, microparticles, pellets,microspheres, etc.), in a sachet or other suitable discreet packagingunits. A particulate formulation will be mixed with tap water shortlybefore administration. In one embodiment, the composition may be mixedwith 50 mL water prior to administration. In another embodiment, thecomposition is an oral pharmaceutical composition.

In various embodiments, the composition includes gamma-hydroxybutyratepresent in a unit dose of at least 4.5 g, at least 6.0 g, at least 7.5g, or at least 9.0 g. In various embodiments, the composition includesgamma-hydroxybutyrate present in a unit dose of more than 4.5 g, morethan 6.0 g, more than 7.5 g, or more than 9.0 g. In one embodiment, theformulation includes 6 g gamma-hydroxybutyrate. In another embodiment,the formulation includes 9 g gamma-hydroxybutyrate.

In one embodiment, the formulation comprises immediate release andmodified release portions, wherein: (a) the modified release portioncomprises coated microparticles of gamma-hydroxybutyrate; and (b) theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 10/90 to 65/35.

In one embodiment, the formulation comprises immediate release andmodified release portions, wherein: (a) the modified release portioncomprises coated microparticles of gamma-hydroxybutyrate; and (b) theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 40/60 to 60/40.

In another embodiment, the formulation comprises immediate release andmodified release portions, wherein: (a) the modified release portioncomprises coated microparticles of gamma-hydroxybutyrate; (b) thecoating of said modified release particles of gamma-hydroxybutyratecomprises a polymer carrying free carboxylic groups and a hydrophobiccompound having a melting point equal or greater than 40° C.; and (c)the ratio of gamma-hydroxybutyrate in the immediate release portion andthe modified release portion is from 10/90 to 65/35 or 40/60 to 60/40.

In another embodiment, the formulation comprises immediate release andmodified release portions, wherein: (a) the modified release portioncomprises coated microparticles of gamma-hydroxybutyrate; (b) thecoating of said modified release particles of gamma-hydroxybutyratecomprises a polymer carrying free carboxylic groups and a hydrophobiccompound having a melting point equal or greater than 40° C.; (c) theweight ratio of the hydrophobic compound to the polymer carrying freecarboxylic groups is from 0.4 to 4; (d) the ratio ofgamma-hydroxybutyrate in the immediate release portion and the modifiedrelease portion is from 10/90 to 65/35 or 40/60 to 60/40; and (e) thefilm coating is from 10 to 50% of the weight of the microparticles.

In another embodiment the formulation comprises immediate release andmodified release portions, wherein: (a) the modified release portioncomprises coated particles of gamma-hydroxybutyrate; (b) the coating ofsaid modified release particles of gamma-hydroxybutyrate comprises apolymer carrying free carboxylic groups having a pH trigger of from 5.5to 6.97 and a hydrophobic compound having a melting point equal orgreater than 40° C.; (c) the weight ratio of the hydrophobic compound tothe polymer carrying free carboxylic groups is from 0.4 to 4; (d) theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 10/90 to 65/35 or 40/60 to 60/40; and(e) the coating is from 10 to 50% of the weight of the particles.

In an embodiment, the polymer carrying free carboxylic groups comprisesfrom 100% poly (methacrylic acid, ethyl acrylate) 1:1 and 0% poly(methacrylic acid, methylmethacrylate) 1:2 to 2% poly (methacrylic acid,ethyl acrylate) 1:1 and 98% poly (methacrylic acid, methylmethacrylate)1:2; and the hydrophobic compound comprises hydrogenated vegetable oil.

In an embodiment, the formulation includes excipients to improve theviscosity and the pourability of the mixture of the particulateformulation with tap water. As such, the particulate formulationcomprises, besides the immediate release and modified release particlesof gamma-hydroxybutyrate, one or more suspending or viscosifying agentsor lubricants.

Suspending or viscosifying agents may be chosen from the groupconsisting of xanthan gum, medium viscosity sodium carboxymethylcellulose, mixtures of microcrystalline cellulose and sodiumcarboxymethyl cellulose, mixtures of microcrystalline cellulose and guargum, medium viscosity hydroxyethyl cellulose, agar, sodium alginate,mixtures of sodium alginate and calcium alginate, gellan gum,carrageenan gum grade iota, kappa or lambda, and medium viscosityhydroxypropylmethyl cellulose.

Medium viscosity sodium carboxymethyl cellulose corresponds to grade ofsodium carboxymethyl cellulose whose viscosity, for a 2% solution inwater at 25° C., is greater than 200 mPa·s and lower than 3100 mPa·s.

Medium viscosity hydroxyethyl cellulose corresponds to a grade ofhydroxyethyl cellulose whose viscosity, for a 2% solution in water at25° C., is greater than 250 mPa·s and lower than 6500 mPa·s. Mediumviscosity hydroxypropylmethyl cellulose corresponds to a grade ofhydroxypropylmethyl cellulose whose viscosity, for a 2% solution inwater at 20° C., is greater than 80 mPa·s. and lower than 3800 mPa·s.

In one embodiment, the suspending or viscosifying agents are xanthangum, especially Xantural 75™ from Kelco, hydroxyethylcellulose,especially Natrosol 250M™ from Ashland, Kappa carrageenan gum,especially Gelcarin PH812™ from FMC Biopolymer, and lambda carrageenangum, especially Viscarin PH209™ from FMC Biopolymer.

In an embodiment, the composition of gamma-hydroxybutyrate comprisesfrom 1 to 15% of viscosifying or suspending agents. In otherembodiments, the composition of gamma-hydroxybutyrate comprisesviscosifying or suspending agents in an amount from 2 to 10%, from 2 to5%, or from 2 to 3% of the formulation.

In an embodiment, the composition of gamma-hydroxybutyrate is in theform of a powder that is intended to be dispersed in water prior toadministration and further comprises from 1 to 15% of a suspending orviscosifying agent selected from a mixture of xanthan gum, carrageenangum and hydroxyethylcellulose or xanthan gum and carrageenan gum.

In an embodiment, the composition of gamma-hydroxybutyrate is in theform of a powder that is intended to be dispersed in water prior toadministration and further comprises: from 1.2 to 15% of an acidifyingagent selected from malic acid and tartaric acid; and from 1 to 15% of asuspending or viscosifying agent selected from a mixture of xanthan gum,carrageenan gum and hydroxyethylcellulose or xanthan gum and carrageenangum.

In one embodiment, the composition of gamma-hydroxybutyrate comprisesabout 1% of lambda carrageenan gum or Viscarin PH209™, about 1% ofmedium viscosity grade of hydroxyethyl cellulose or Natrosol 250M™, andabout 0.7% of xanthan gum or Xantural 75™. For a 4.5 g dose unit, thesepercentages will typically equate to about 50 mg xanthan gum (Xantural75™), about 75 mg carragenan gum (Viscarin PH209™), and about 75 mghydroxyethylcellulose (Natrasol 250M™).

Alternative packages of viscosifying or suspending agents, for a 4.5 gdose, include about 50 mg xanthan gum (Xantural 75™) and about 100 mgcarragenan gum (Gelcarin PH812™), or about 50 mg xanthan gum (Xantural75™), about 75 mg hydroxyethylcellulose (Natrasol 250M™), and about 75mg carragenan gum (Viscarin PH109™).

In an embodiment, the composition of gamma-hydroxybutyrate furthercomprises a lubricant or a glidant, besides the immediate release andmodified release particles of gamma-hydroxybutyrate. In variousembodiments, the lubricants and glidants are chosen from the groupconsisting of salts of stearic acid, in particular magnesium stearate,calcium stearate or zinc stearate, esters of stearic acid, in particularglyceryl monostearate or glyceryl palmitostearate, stearic acid,glycerol behenate, sodium stearyl fumarate, talc, and colloidal silicondioxide. In one embodiment, the lubricant or glidant is magnesiumstearate. The lubricant or glidant may be used in the particulateformulation in an amount of from 0.1 to 5%. In one embodiment, theamount of lubricant or glidant is about 0.5%. For example, thecomposition of gamma-hydroxybutyrate may include about 0.5% of magnesiumstearate.

A composition of gamma-hydroxybutyrate may further include an acidifyingagent. The acidifying agent helps to ensure that the release profile ofthe formulation in 0.1N HCl will remain substantially unchanged for atleast 15 minutes after mixing, which is approximately the maximum lengthof time a patient might require before consuming the dose after mixingthe formulation with tap water.

In one embodiment, the formulation is a powder, and further comprisingan acidifying agent and a suspending or viscosifying agent in the weightpercentages recited herein.

The acidifying agents may be chosen from the group consisting of malicacid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid,phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid,and benzoic acid. In various embodiments, the acidifying agent ispresent in the formulation from 1.2 to 15%, from 1.2 to 10%, or from 1.2to 5%. In one embodiment, the acidifying agents are tartaric acid andmalic acid. In another embodiment, the acidifying agent is malic acid.

When tartaric acid is employed, it may be employed in an amount of from1 to 10%, from 2.5 to 7.5%, or about 5%. In various embodiments, theamount of malic acid in the composition of gamma-hydroxybutyrate is from1.2 to 15%, from 1.2 to 10%, from 1.2 to 5%, or from 1.6% or 3.2%. Inone embodiment, the amount of malic acid in the composition of gammahydroxybutyrate is about 1.6%.

The composition of gamma-hydroxybutyrate includes an immediate releaseportion and a modified release portion of gamma-hydroxybutyrate, and inan embodiment, the formulation is a particulate formulation thatincludes a plurality of immediate release gamma-hydroxybutyrateparticles and a plurality of modified release gamma-hydroxybutyrateparticles. The molar ratio of gamma-hydroxybutyrate in the immediaterelease and modified release portions ranges from 0.11:1 to 1.86:1, from0.17:1 to 1.5:1, from 0.25:1 to 1.22:1, from 0.33:1 to 1.22:1, from0.42:1 to 1.22:1, from 0.53:1 to 1.22:1, from 0.66:1 to 1.22:1, from0.66:1 to 1.5:1, from 0.8:1 to 1.22:1. In one embodiment, the molarratio of gamma-hydroxybutyrate in the immediate release and modifiedrelease portions is about 1:1. The molar percentage ofgamma-hydroxybutyrate in the immediate release portion relative to thetotal of gamma-hydroxybutyrate in the formulation ranges from 10% to65%, from 15 to 60%, from 20 to 55%, from 25 to 55%, from 30 to 55%,from 35 to 55%, from 40 to 55%, from 40 to 60%, or from 45 to 55%. Inone embodiment, the molar percentage of gamma-hydroxybutyrate in theimmediate release portion relative to the total of gamma-hydroxybutyratein the formulation ranges from 40% to 60%. In an embodiment, the molarpercentage of the gamma-hydroxybutyrate in the immediate release portionrelative to the total of gamma-hydroxybutyrate in the formulation isabout 50%. The molar percentage of gamma-hydroxybutyrate in the modifiedrelease portion relative to the total of gamma-hydroxybutyrate in theformulation ranges from 90% to 35%, from 85 to 40%, from 80 to 45%, from75 to 45%, from 70 to 45%, from 65 to 45%, from 60 to 45%, from 60 to40%, or from 55 to 45%. In an embodiment, the molar percentage ofgamma-hydroxybutyrate in the modified release portion relative to thetotal of gamma-hydroxybutyrate in the formulation ranges from 60% to40%. In one embodiment, the molar ratio of the gamma-hydroxybutyrate inthe modified release portion relative to the total ofgamma-hydroxybutyrate in the formulation is about 50%. The weightpercentage of the IR microparticles relative to the total weight of IRmicroparticles and MR microparticles ranges from 7.2% to 58.2%, from11.0% to 52.9%, from 14.9% to 47.8%, from 18.9% to 47.8%, from 23.1% to47.8%, from 27.4% to 47.8%, from 31.8% to 47.8%, from 31.8% to 52.9%, orfrom 36.4% to 47.8%. In other embodiments, the weight percentage of theIR microparticles relative to the total weight of IR microparticles andMR microparticles ranges from 5.9% to 63.2%, from 9.1% to 58.1%, from12.4% to 53.1%, from 19.9% to 53.1%, from 19.6% to 53.1%, from 23.4% to53.1%, from 27.4% to 53.1%, or from 27.4% to 58.1%. In one embodiment,the weight percentage of the IR microparticles relative to the totalweight of IR microparticles and MR microparticles ranges from 31.7% to53.1%.

In an embodiment, the finished formulation comprises 50% of its sodiumoxybate content in immediate-release particles consisting of 80.75% w/wof sodium oxybate, 4.25% w/w of Povidone K30 and 15% of microcrystallinecellulose spheres with a volume mean diameter of about 95 microns to 450microns and 50% of its sodium oxybate content in modified releaseparticles consisting of 10.5% w/w of microcrystalline cellulose sphereswith a volume mean diameter of about 95 microns to about 450 microns,layered with 56.5% w/w of sodium oxybate mixed with 3% w/w of Povidone™K30 and finally coated with a coating composition consisting of 18% w/wof hydrogenated vegetable oil (Lubritab™ or equivalent), 4% ofmethacrylic acid copolymer type C (Eudragit™ L100-55 or equivalent) and8% of methacrylic acid copolymer type B (Eudragit™ S100 or equivalent).

In an embodiment, the finished formulation comprises 50% of its sodiumoxybate content in immediate-release particles consisting of 80.75% w/wof sodium oxybate, 4.25% w/w of Povidone K30 and 15% of microcrystallinecellulose spheres with a volume mean diameter of about 95 microns to 170microns and 50% of its sodium oxybate content in modified releaseparticles consisting of 10.5% w/w of microcrystalline cellulose sphereswith a volume mean diameter of about 95 microns to about 170 microns,layered with 56.5% w/w of sodium oxybate mixed with 3% w/w of Povidone™K30 and finally coated with a coating composition consisting of 18% w/wof hydrogenated vegetable oil (Lubritab™ or equivalent), 4% ofmethacrylic acid copolymer type C (Eudragit™ L100-55 or equivalent) and8% of methacrylic acid copolymer type B (Eudragit™ S100 or equivalent).

In an embodiment, the finished formulation comprises 50% of its sodiumoxybate content in immediate-release particles consisting of 80.75% w/wof sodium oxybate, 4.25% w/w of Povidone K30 and 15% of microcrystallinecellulose spheres with a volume mean diameter of about 95 microns toabout 450 microns and 50% of its sodium oxybate content in modifiedrelease particles consisting of 11.3% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 450microns, layered with 60.5% w/w of sodium oxybate mixed with 3.2% w/w ofPovidone™ K30 and finally coated with a coating composition consistingof 15% w/w of hydrogenated vegetable oil (Lubritab™ or equivalent),0.75% of methacrylic acid copolymer type C (Eudragit™ L100-55 orequivalent) and 9.25% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent).

In an embodiment, the finished formulation comprises 50% of its sodiumoxybate content in immediate-release particles consisting of 80.75% w/wof sodium oxybate, 4.25% w/w of Povidone™ K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 170 microns and 50% of its sodium oxybate content inmodified release particles consisting of 11.3% w/w of microcrystallinecellulose spheres with a volume mean diameter of about 95 microns toabout 170 microns, layered with 60.5% w/w of sodium oxybate mixed with3.2% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 15% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 0.75% of methacrylic acid copolymer type C (Eudragit™L100-55 or equivalent) and 9.25% of methacrylic acid copolymer type B(Eudragit™ S100 or equivalent).

In an embodiment, the finished formulation comprises 50% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 450 microns and 50% ofits gamma-hydroxybutyrate content in modified release particlesconsisting of 10.5% w/w of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 450 microns, layeredwith 56.5% w/w of sodium oxybate mixed with 3% w/w of Povidone™ K30 andfinally coated with a coating composition consisting of 18% w/w ofhydrogenated vegetable oil (Lubritab™ or equivalent), 4% of methacrylicacid copolymer type C (Eudragit™ L100-55 or equivalent) and 8% ofmethacrylic acid copolymer type B (Eudragit™ S100 or equivalent).

In an embodiment, the finished formulation comprises 50% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 170 microns and 50% ofits gamma-hydroxybutyrate content in modified release particlesconsisting of 10.5% w/w of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 170 microns, layeredwith 56.5% w/w of sodium oxybate mixed with 3% w/w of Povidone™ K30 andfinally coated with a coating composition consisting of 18% w/w ofhydrogenated vegetable oil (Lubritab™ or equivalent), 4% of methacrylicacid copolymer type C (Eudragit™ L100-55 or equivalent) and 8% ofmethacrylic acid copolymer type B (Eudragit™ S100 or equivalent).

In an embodiment, the finished formulation comprises 16.7% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 450 microns, 16.7% ofits gamma-hydroxybutyrate content in immediate-release particlesconsisting of 80.75% w/w of magnesium salt of gamma-hydroxybutyric acid,4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose sphereswith a volume mean diameter of about 95 microns to about 450 microns,16.7% of its gamma-hydroxybutyrate content in immediate-releaseparticles consisting of 80.75% w/w of calcium salt ofgamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 450 microns and 50% of its gamma-hydroxybutyratecontent in modified release particles consisting of 10.5% w/w ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 450 microns, layered with 56.5% w/w of sodiumoxybate mixed with 3% w/w of Povidone™ K30 and finally coated with acoating composition consisting of 18% w/w of hydrogenated vegetable oil(Lubritab™ or equivalent), 4% of methacrylic acid copolymer type C(Eudragit™ L100-55 or equivalent) and 8% of methacrylic acid copolymertype B (Eudragit™ S100 or equivalent).

In an embodiment, the finished formulation comprises 16.7% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 170 microns, 16.7% ofits gamma-hydroxybutyrate content in immediate-release particlesconsisting of 80.75% w/w of magnesium salt of gamma-hydroxybutyric acid,4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose sphereswith a volume mean diameter of about 95 microns to about 170 microns,16.7% of its gamma-hydroxybutyrate content in immediate-releaseparticles consisting of 80.75% w/w of calcium salt ofgamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 170 microns and 50% of its gamma-hydroxybutyratecontent in modified release particles consisting of 10.5% w/w ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 170 microns, layered with 56.5% w/w of sodiumoxybate mixed with 3% w/w of Povidone™ K30 and finally coated with acoating composition consisting of 18% w/w of hydrogenated vegetable oil(Lubritab™ or equivalent), 4% of methacrylic acid copolymer type C(Eudragit™ L100-55 or equivalent) and 8% of methacrylic acid copolymertype B (Eudragit™ S100 or equivalent).

In an embodiment, the finished formulation comprises 50% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 450 microns and 50% ofits gamma-hydroxybutyrate content in modified release particlesconsisting of 10.5% w/w of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 450 microns, layeredwith 56.5% w/w of calcium salt of gamma-hydroxybutyric acid mixed with3% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent).

In an embodiment, the finished formulation comprises 50% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 170 microns and 50% ofits gamma-hydroxybutyrate content in modified release particlesconsisting of 10.5% w/w of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 170 microns, layeredwith 56.5% w/w of calcium salt of gamma-hydroxybutyric acid mixed with3% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent).

Other Characteristics of Immediate Release Portion

The immediate release portion of the formulation can take any formcapable of achieving an immediate release of the gamma-hydroxybutyratewhen ingested. For example, when the formulation is a particulateformulation, the formulation can include unmodified “raw”gamma-hydroxybutyrate, rapidly dissolving gamma-hydroxybutyrategranules, particles or microparticles comprised of a core covered by agamma-hydroxybutyrate loaded layer containing a binder such as povidone.

The IR granules or particles of gamma-hydroxybutyrate may be made usingany manufacturing process suitable to produce the required particles,including:

-   -   agglomeration of the gamma-hydroxybutyrate sprayed in the molten        state, such as the Glatt ProCel™ technique,    -   extrusion and spheronization of the gamma-hydroxybutyrate,        optionally with one or more physiologically acceptable        excipients,    -   wet granulation of the gamma-hydroxybutyrate, optionally with        one or more physiologically acceptable excipients,    -   compacting of the gamma-hydroxybutyrate, optionally with one or        more physiologically acceptable excipients,    -   granulation and spheronization of the gamma-hydroxybutyrate,        optionally with one or more physiologically acceptable        excipients, the spheronization being carried out for example in        a fluidized bed apparatus equipped with a rotor, in particular        using the Glatt CPS™ technique,    -   spraying of the gamma-hydroxybutyrate, optionally with one or        more physiologically acceptable excipients, for example in a        fluidized bed type apparatus equipped with zig-zag filter, in        particular using the Glatt MicroPx™ technique, or    -   spraying, for example in a fluidized bed apparatus optionally        equipped with a partition tube or Wurster tube, the        gamma-hydroxybutyrate, optionally with one or more        physiologically acceptable excipients, in dispersion or in        solution in an aqueous or organic solvent on a core.

The immediate release portion of the formulation is in the form ofmicroparticles comprising the immediate release gamma-hydroxybutyrateand optional pharmaceutically acceptable excipients. In an embodiment,the immediate release microparticles of gamma-hydroxybutyrate have avolume mean diameter D(4.3) of from 10 to 1000 microns. In otherembodiments, the immediate release microparticles ofgamma-hydroxybutyrate have a volume mean diameter D(4.3) of from 95 to600 microns. In additional embodiments, the immediate releasemicroparticles of gamma-hydroxybutyrate have a volume mean diameterD(4.3) of from 150 to 400 microns. In one embodiment, their volume meandiameter is about 270 microns.

The immediate release particles of gamma-hydroxybutyrate may include acore and a layer deposited on the core that contains thegamma-hydroxybutyrate. The core may be any particle chosen from thegroup consisting of:

-   -   crystals or spheres of lactose, sucrose (such as Compressuc™ PS        from Tereos), microcrystalline cellulose (such as Avicel™ from        FMC Biopolymer, Cellet™ from Pharmatrans or Celphere™ from Asahi        Kasei), sodium chloride, calcium carbonate (such as Omyapure™ 35        from Omya), sodium hydrogen carbonate, dicalcium phosphate (such        as Dicafos™ AC 92-12 from Budenheim) or tricalcium phosphate        (such as Tricafos™ SC93-15 from Budenheim);    -   composite spheres or granules, for example sugar spheres        comprising sucrose and starch (such as Suglets™ from NP Pharm),        spheres of calcium carbonate and starch (such as Destab™ 90 S        Ultra 250 from Particle Dynamics) or spheres of calcium        carbonate and maltodextrin (such as Hubercal™ CCG4100 from        Huber).

The core can also comprise other particles of pharmaceuticallyacceptable excipients such as particles of hydroxypropyl cellulose (suchas Klucel™ from Aqualon Hercules), guar gum particles (such as Grinsted™Guar from Danisco), xanthan particles (such as Xantural™ 180 from CPKelco).

According to a particular embodiment of the invention, the cores aresugar spheres or microcrystalline cellulose spheres, such as Cellets™90, Cellets™ 100 or Cellets™ 127 marketed by Pharmatrans, or alsoCelphere™ OP 203, Celphere™ CP305, Celphere™ SCP 100. In one embodiment,the core is a microcrystalline cellulose sphere. For example, the coremay be a Cellets™ 127 from Pharmatrans.

In various embodiments, the core has a mean volume diameter of about 95to about 450 microns, about 95 to about 170 microns, or about 140microns.

The layer deposited onto the core comprises the immediate releasegamma-hydroxybutyrate. In an embodiment, the layer also comprises abinder, which may be chosen from the group consisting of:

-   -   low molecular weight hydroxypropyl cellulose (such as Klucel™ EF        from Aqualon-Hercules), low molecular weight hydroxypropyl        methylcellulose (or hypromellose) (such as Methocel™ E3 or E5        from Dow), or low molecular weight methylcellulose (such as        Methocel™ A15 from Dow);    -   low molecular weight polyvinyl pyrrolidone (or povidone) (such        as Plasdone™ K29/32 from ISP or Kollidon™ 30 from BASF), vinyl        pyrrolidone and vinyl acetate copolymer (or copovidone) (such as        Plasdone™ S630 from ISP or Kollidon™ VA 64 from BASF);    -   dextrose, pregelatinized starch, maltodextrin; and mixtures        thereof.

Low molecular weight hydroxypropyl cellulose corresponds to grades ofhydroxypropyl cellulose having a molecular weight of less than 800,000g/mol, less than or equal to 400,000 g/mol, or less than or equal to100,000 g/mol. Low molecular weight hydroxypropyl methylcellulose (orhypromellose) corresponds to grades of hydroxypropyl methylcellulose thesolution viscosity of which, for a 2% solution in water and at 20° C.,is less than or equal to 1,000 mPa·s, less than or equal to 100 mPa·s,or less than or equal to 15 mPa·s. Low molecular weight polyvinylpyrrolidone (or povidone) corresponds to grades of polyvinyl pyrrolidonehaving a molecular weight of less than or equal to 1,000,000 g/mol, lessthan or equal to 800,000 g/mol, or less than or equal to 100,000 g/mol.

In some embodiments, the binding agent is chosen from low molecularweight polyvinylpyrrolidone or povidone (for example, Plasdone™ K29/32from ISP), low molecular weight hydroxypropyl cellulose (for example,Klucel™ EF from Aqualon-Hercules), low molecular weight hydroxypropylmethylcellulose or hypromellose (for example, Methocel™ E3 or E5 fromDow) and mixtures thereof.

In one embodiment, the binder is povidone K30 or K29/32, especiallyPlasdone™ K29/32 from ISP. The binder may be present in an amount of 0to 80%, 0 to 70%, 0 to 60%, 0 to 50%, 0 to 40%, 0 to 30%, 0 to 25%, 0 to20%, 0 to 15%, 0 to 10%, or from 1 to 9% of binder based on the totalweight of the immediate release coating. In an embodiment, the binder ispresent in an amount of 5% based on the total weight of the immediaterelease coating. In one embodiment, the amount of binder is 5% of binderover the total mass of gamma-hydroxybutyrate and binder.

The layer deposited on the core can represent at least 10% by weight,and even greater than 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,80, 85 or 90% by weight of the total weight of the immediate releaseparticle of gamma-hydroxybutyrate. In one embodiment, the layerdeposited on the core represents about 85% of the weight of theimmediate release particle of gamma-hydroxybutyrate.

According to an embodiment, the immediate-release particles comprise80.75% w/w of gamma-hydroxybutyrate, 4.25% w/w of Povidone K30 and 15%of microcrystalline cellulose spheres.

According to another embodiment, the immediate-release particlescomprise 80.75% w/w of gamma-hydroxybutyrate, 4.25% w/w of Povidone K30and 15% of microcrystalline cellulose spheres with a volume meandiameter of about 95 microns to about 450 microns.

According to yet another embodiment, the immediate-release particlescomprise 80.75% w/w of gamma-hydroxybutyrate, 4.25% w/w of Povidone K30and 15% of microcrystalline cellulose spheres with a volume meandiameter of about 95 microns to about 170 microns.

According to an embodiment, the immediate-release particles comprise80.75% w/w of sodium oxybate, 4.25% w/w of Povidone K30 and 15% ofmicrocrystalline cellulose spheres.

According to another embodiment, the immediate-release particlescomprise 80.75% w/w of potassium salt of gamma-hydroxybutyric acid,4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres.

According to another embodiment, the immediate-release particlescomprise 80.75% w/w of calcium salt of gamma-hydroxybutyric acid, 4.25%w/w of Povidone K30 and 15% of microcrystalline cellulose spheres.

According to another embodiment, the immediate-release particlescomprise 80.75% w/w of magnesium salt of gamma-hydroxybutyric acid,4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres.

According to another embodiment, the immediate-release particles aremanufactured by dissolving the gamma-hydroxybutyrate and the PovidoneK30 in a mixture of water/ethanol 40/60 w/w and spraying the resultingsolution onto the surface of the microcrystalline cellulose spheres.

Other Characteristics of Modified Release Portion

The modified release portion may be any formulation that provides thedesired in vitro dissolution profile of gamma-hydroxybutyrate. Themodified release portion may include modified release particles,obtained by coating immediate release particles of gamma-hydroxybutyratewith a coating (or coating film) that inhibits the immediate release ofthe gamma-hydroxybutyrate. In one sub-embodiment the modified releaseportion comprises particles comprising: (a) an inert core; (b) acoating; and (c) a layer comprising the gamma hydroxybutyrate interposedbetween the core and the coating.

In an embodiment, the modified release portion comprises atime-dependent release mechanism and a pH-dependent release mechanism.

In an embodiment, the coating film comprises at least one polymercarrying free carboxylic groups, and at least one hydrophobic compoundcharacterized by a melting point equal or greater than 40° C.

The polymer carrying free carboxylic groups may be selected from:(meth)acrylic acid/alkyl (meth)acrylate copolymers or methacrylic acidand methylmethacrylate copolymers or methacrylic acid and ethyl acrylatecopolymers or methacrylic acid copolymers type A, B or C, cellulosederivatives carrying free carboxylic groups, cellulose acetatephthalate, cellulose acetate succinate, hydroxypropyl methyl cellulosephthalate, carboxymethylethyl cellulose, cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetatephthalate, zein, shellac, alginate and mixtures thereof.

In an embodiment, the methacrylic acid copolymers are chosen from thegroup consisting of poly (methacrylic acid, methyl methacrylate) 1:1 orEudragit™ L100 or equivalent, poly (methacrylic acid, ethyl acrylate)1:1 or Eudragit™ L100-55 or equivalent and poly (methacrylic acid,methyl methacrylate) 1:2 or Eudragit™ S100 or equivalent.

In another embodiment the coating comprises a polymer carrying freecarboxylic groups wherein the free carboxylic groups are substantiallyionized at pH 7.5.

The hydrophobic compound with a melting point equal or greater than 40°C. may be selected from the group consisting of hydrogenated vegetableoils, vegetable waxes, wax yellow, wax white, wax microcrystalline,lanolin, anhydrous milk fat, hard fat suppository base, lauroyl macrogolglycerides, polyglyceryl diisostearate, diesters or triesters ofglycerol with a fatty acid, and mixtures thereof.

In various embodiments, the hydrophobic compound with a melting pointequal or greater than 40° C. is chosen from the group of followingproducts: hydrogenated cottonseed oil, hydrogenated soybean oil,hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil,candellila wax, tristearin, tripalmitin, trimyristin, yellow wax, hardfat or fat that is useful as suppository bases, anhydrous dairy fats,lanolin, glyceryl palmitostearate, glyceryl stearate, lauryl macrogolglycerides, polyglyceryl diisostearate, diethylene glycol monostearate,ethylene glycol monostearate, omega 3 fatty acids, and mixtures thereof.For example, the hydrophobic compound may include hydrogenatedcottonseed oil, hydrogenated soybean oil, hydrogenated palm oil,glyceryl behenate, hydrogenated castor oil, candelilla wax, tristearin,tripalmitin, trimyristin, beeswax, hydrogenated poly-1 decene, carnaubawax, and mixtures thereof.

In practice, and without this being limiting, the hydrophobic compoundwith a melting point equal or greater than 40° C. may be chosen from thegroup of products sold under the following trademarks: Dynasan™,Cutina™, Hydrobase™ Dub™, Castorwax™, Croduret™, Compritol™, Sterotex™,Lubritab™, Apifil™ Akofine™, Softisan™, Hydrocote™, Livopol™, SuperHartolan™, MGLA™, Corona™ Protalan™, Akosoft™, Akosol™, Cremao™,Massupol™, Novata™, Suppocire™ Wecobee™, Witepsol™, Lanolin™,Incromega™, Estaram™, Suppoweiss™ Gelucire™, Precirol™, Emulcire™,Plurol Diisostearique™, Geleol™, Hydrine™ Monthyle™, Kahlwax™ andmixtures thereof. In an embodiment, the hydrophobic compound with amelting point equal or greater than 40° C. may be chosen from the groupof products sold under the following trademarks: Dynasan™P60,Dynasan™114, Dynasan™116, Dynasan™118, Cutina™ HR, Hydrobase™ 66-68,Dub™ HPH, Compritol™ 888, Sterotex™ NF, Sterotex™ K, Lubritab™, andmixtures thereof.

A particularly suitable coating is composed of a mixture of hydrogenatedvegetable oil and a methacrylic acid copolymer. The exact structure andamount of each component, and the amount of coating applied to theparticle, controls the release rate and release triggers. Eudragit®methacrylic acid copolymers, namely the methacrylic acid-methylmethacrylate copolymers and the methacrylic acid-ethyl acrylatecopolymers, have a pH-dependent solubility: typically, the pH triggeringthe release of the active ingredient from the microparticles is set bythe choice and mixture of appropriate Eudragit® polymers. In the case ofgamma hydroxybutyrate modified release microparticles, the theoreticalpH triggering the release is from 5.5 to 6.97 or from 5.5 to 6.9. By “pHtrigger” is meant the minimum pH above which dissolution of the polymeroccurs.

In a particular embodiment, the coating comprises a hydrophobic compoundwith a melting point equal or greater than 40° C. and a polymer carryingfree carboxylic groups are present in a weight ratio from 0.4 to 4, from0.5 to 4, from 0.6 to 2.5, from 0.67 to 2.5, from 0.6 to 2.33, or from0.67 to 2.33. In one embodiment, the weight ratio is about 1.5.

A particularly suitable coating is composed of a mixture of hydrogenatedvegetable oil and a methacrylic acid copolymer with a theoretical pHtriggering the release from 6.5 up to 6.97 in a weight ratio from 0.4 to4, from 0.5 to 4, from 0.6 to 2.5, from 0.67 to 2.5, from 0.6 to 2.33,or from 0.67 to 2.33. In one embodiment, the weight ratio may be about1.5.

The modified release particles of gamma-hydroxybutyrate have a volumemean diameter of from 100 to 1200 microns, from 100 to 500 microns, orfrom 200 to 800 microns. In one embodiment, the modified releaseparticles of gamma-hydroxybutyrate have a volume mean diameter of about320 microns.

The coating can represent 10 to 50%, 15 to 45%, 20 to 40%, or 25 to 35%by weight of the total weight of the coated modified release particles.In one embodiment, the coating represents 25-30% by weight of the totalweight of the modified release particles of gamma-hydroxybutyrate.

In an embodiment, the coating layer of the modified release particles ofgamma-hydroxybutyrate is obtained by spraying, in particular in afluidized bed apparatus, a solution, suspension or dispersion comprisingthe coating composition as defined previously onto the immediate releaseparticles of gamma-hydroxybutyrate, in particular the immediate releaseparticles of gamma-hydroxybutyrate as previously described. In oneembodiment, the coating is formed by spraying in a fluidized bedequipped with a Wurster or partition tube and according to an upwardspray orientation or bottom spray a solution of the coating excipientsin hot isopropyl alcohol.

According to an embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 10.5% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 450microns, layered with 56.5% w/w of gamma-hydroxybutyrate mixed with 3%w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent), all percentages expressed based on the total weightof the final modified release particles of gamma-hydroxybutyrate.

According to an embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 10.5% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 170microns, layered with 56.5% w/w of gamma-hydroxybutyrate mixed with 3%w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent), all percentages expressed based on the total weightof the final modified release particles of gamma-hydroxybutyrate.

According to an embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 10.5% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 450microns, layered with 56.5% w/w of sodium oxybate mixed with 3% w/w ofPovidone™ K30 and finally coated with a coating composition consistingof 18% w/w of hydrogenated vegetable oil (Lubritab™ or equivalent), 4%of methacrylic acid copolymer type C (Eudragit™ L100-55 or equivalent)and 8% of methacrylic acid copolymer type B (Eudragit™ S100 orequivalent), all percentages expressed based on the total weight of thefinal modified release particles of sodium oxybate.

According to an embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 10.5% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 170microns, layered with 56.5% w/w of sodium oxybate mixed with 3% w/w ofPovidone™ K30 and finally coated with a coating composition consistingof 18% w/w of hydrogenated vegetable oil (Lubritab™ or equivalent), 4%of methacrylic acid copolymer type C (Eudragit™ L100-55 or equivalent)and 8% of methacrylic acid copolymer type B (Eudragit™ S100 orequivalent), all percentages expressed based on the total weight of thefinal modified release particles of sodium oxybate.

According to another embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 11.3% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 450microns, layered with 60.5% w/w of gamma-hydroxybutyrate mixed with 3.2%w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 15% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 0.75% of methacrylic acid copolymer type C (Eudragit™L100-55 or equivalent) and 9.25% of methacrylic acid copolymer type B(Eudragit™ S100 or equivalent).

According to another embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 11.3% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 170microns, layered with 60.5% w/w of gamma-hydroxybutyrate mixed with 3.2%w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 15% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 0.75% of methacrylic acid copolymer type C (Eudragit™L100-55 or equivalent) and 9.25% of methacrylic acid copolymer type B(Eudragit™ S100 or equivalent).

According to another embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 11.3% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 450microns, layered with 60.5% w/w of sodium oxybate mixed with 3.2% w/w ofPovidone™ K30 and finally coated with a coating composition consistingof 15% w/w of hydrogenated vegetable oil (Lubritab™ or equivalent),0.75% of methacrylic acid copolymer type C (Eudragit™ L100-55 orequivalent) and 9.25% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent).

According to another embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 11.3% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 170microns, layered with 60.5% w/w of sodium oxybate mixed with 3.2% w/w ofPovidone™ K30 and finally coated with a coating composition consistingof 15% w/w of hydrogenated vegetable oil (Lubritab™ or equivalent),0.75% of methacrylic acid copolymer type C (Eudragit™ L100-55 orequivalent) and 9.25% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent).

Packaging

The composition of gamma-hydroxybutyrate may be supplied in sachets orstick-packs comprising a particulate formulation. The sachets may beavailable in several different doses, comprising gamma-hydroxybutyratein amounts equivalents to 0.5 g, 1.0 g, 1.5 g, 3.0 g, 4.5 g, 6.0 g, 7.5g, 9.0 g, 10.5 g and/or 12 g of sodium oxybate. Depending on the doserequired, one or more of these sachets may be opened, and its contentsmixed with tap water to provide the nightly dose ofgamma-hydroxybutyrate.

Methods of Treatment

Further provided herein is a method of treating a disorder treatablewith gamma-hydroxybutyrate in a human subject in need thereof comprisingorally administering, less than two hours after eating, a single bedtimedaily dose to said human amounts of gamma-hydroxybutyrate equivalent tofrom 3.0 to 12.0 g of sodium oxybate in the composition. Furtherprovided herein are methods of treating narcolepsy, types 1 and/or 2, byorally administering at bedtime a therapeutically effective amount of agamma-hydroxybutyrate formulation characterized by the novelgamma-hydroxybutyrate pharmacokinetic properties of the composition whenadministered less than two hours after eating. In an embodiment, thecomposition of the present invention is effective to treat narcolepsyType 1 or Type 2, wherein the treatment of narcolepsy is defined asreducing excessive daytime sleepiness or reducing the frequency ofcataplectic attacks. The therapeutically effective amount may includeequivalents from 3.0 to 12.0 g of sodium oxybate. In variousembodiments, the therapeutically effective amount is 4.5, 6.0, 7.5 or9.0 g of sodium oxybate. In one embodiment, the therapeuticallyeffective amount is 6 g or 9 g of sodium oxybate. In variousembodiments, the formulation includes sodium oxybate present in a unitdose of at least 4.5 g, at least 6.0 g, at least 7.5 g, or at least 9.0g. The effectiveness of the treatment may be measured by one or anycombination of the following criteria:

-   -   Increase the mean sleep latency, as determined on the        Maintenance of Wakefulness Test (MWT)    -   Improve the Clinical Global Impression (CGI) rating of        sleepiness    -   Decrease the number of cataplexy attacks (NCA) determined from        the cataplexy frequency item in the Sleep and Symptoms Daily        Diary    -   Decrease the disturbed nocturnal sleep (DNS), the disturbed        nocturnal events or the adverse respiratory events as determined        by polysomnographic (PSG) measures of sleep fragmentation    -   Decrease the excessive daytime sleepiness (EDS) as measured by        patient report via the Epworth Sleepiness Scale (ESS)    -   Decrease the daytime sleepiness as measured by the Maintenance        of Wakefulness Test based on EEG measures of wakefulness    -   Decrease PSG transitions from N/2 to N/3 and REM sleep to wake        and N1 sleep (as determined by C Iber, S Ancoli-Israel, A        Chesson, S F Quan. The AASM Manual for the Scoring of Sleep and        Associated Events. Westchester, Ill.: American Academy of Sleep        Medicine; 2007).    -   Decrease the number of arousals or wakenings, obtained from a        PSG as defined by the American Academy of Sleep Medicine    -   Improve the sleep quality, obtained from one or more of (i) the        Sleep and Symptom Daily Diary, (ii) Visual Analog Scale (VAS)        for sleep quality and sleep diary, and (iii) VAS for the        refreshing nature of sleep    -   Decrease the Hypnagogic Hallucinations (HH) or sleep paralysis        (SP) symptoms in NT1 narcolepsy patients, as measured by the        Sleep and Symptom Daily Diary

In an embodiment, the treatment using the composition administered lessthan two hours after eating is superior, as measured by any one orcombination of the foregoing criteria, to an equal dose administeredtwice nightly of an immediate release liquid solution of sodium oxybate,with the second dose administered 4 hours after the first dose.

The invention further provides a method of treatment of narcolepsy Type1 or Type 2 wherein, compared to a dosing regimen consisting ofadministering half the dose at t₀ and another half of the dose at t4 hof an immediate release liquid solution of sodium oxybate, a singlebedtime daily dose administration of a therapeutically effective amountof the formulation of the invention has been shown to produce lessconfusion, less depressive syndrome, less incontinence, less nausea orless sleepwalking.

EXAMPLES Example 1. Formulations

Tables 1a-1d provide the qualitative and quantitative compositions ofsodium oxybate IR microparticles, MR microparticles, and mixtures of IRand MR microparticles. The physical structure of the microparticlesshowing the qualitative and quantitative composition of the IR and MRmicroparticles is depicted in FIG. 1.

Briefly, sodium oxybate immediate release (IR) microparticles wereprepared as follows: 1615.0 g of sodium oxybate and 85.0 g ofpolyvinylpyrrolidone (Povidone K30-Plasdone™ K29/32 from ISP) weresolubilized in 1894.3 g of absolute ethyl alcohol and 1262.9 g of water.The solution was entirely sprayed onto 300 g of microcrystallinecellulose spheres (Cellets™ 127) in a fluid bed spray coater apparatus.IR Microparticles with volume mean diameter of about 270 microns wereobtained.

Sodium oxybate modified release (MR) microparticles were prepared asfollows: 22.8 g of methacrylic acid copolymer Type C (Eudragit™L100-55), 45.8 g of methacrylic acid copolymer Type B (Eudragit™ S100),102.9 g of hydrogenated cottonseed oil (Lubritab™), were dissolved in1542.9 g of isopropanol at 78° C. The solution was sprayed entirely onto400.0 g of the sodium oxybate IR microparticles described above in afluid bed spray coater apparatus with an inlet temperature of 48° C.,spraying rate around 11 g per min and atomization pressure of 1.3 bar.MR microparticles were dried for two hours with inlet temperature set to56° C. MR microparticles with mean volume diameter of about 320 micronswere obtained.

The finished composition, which contains a 50:50 mixture of MR and IRmicroparticles calculated on their sodium oxybate content, was preparedas follows: 353.36 g of the above IR microparticles, 504.80 g of theabove MR microparticles, 14.27 g of malic acid (D/L malic acid), 6.34 gof xanthan gum (Xantural™ 75 from Kelco), 9.51 g of carrageenan gum(Viscarin™ PH209 from FMC Biopolymer), 9.51 g of hydroxyethylcellulose(Natrosol™ 250 M from Ashland) and 4.51 g of magnesium stearate weremixed. Individual samples of 7.11 g (corresponding to a 4.5 g dose ofsodium oxybate with half of the dose as immediate-release fraction andhalf of the dose as modified release fraction) were weighed.

TABLE 1a Composition of IR Microparticles Quantity per ComponentFunction 2.25 g dose (g) Sodium oxybate Drug substance 2.25 Microcrystalline Core 0.418 cellulose spheres Povidone K30 Binder andexcipient 0.118 in diffusion coating Ethyl alcohol Solvent Eliminatedduring processing Purified water Solvent Eliminated during processingTotal 2.786

TABLE 1b Composition of MR Microparticles Quantity per ComponentFunction 4.5 g dose (g) IR Microparticles Core of MR 2.786microparticles Hydrogenated Coating excipient 0.716 Vegetable OilMethacrylic acid Coating excipient 0.159 Copolymer Type C Methacrylicacid Coating excipient 0.318 Copolymer Type B Isopropyl alcohol SolventEliminated during processing Total 3.981

TABLE 1c Qualitative Finished Composition Quantity per ComponentFunction 4.5 g dose (g) MR microparticles Modified release 3.981fraction of sodium oxybate IR microparticles Immediate release 2.786fraction of sodium oxybate Malic acid Acidifying agent 0.113 Xanthan gumSuspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.036 Total 7.116

TABLE 1d Quantitative finished composition Quantity per ComponentFunction 4.5 g dose (g) Sodium oxybate Drug substance 4.5Microcrystalline cellulose spheres Core 0.836 Povidone K30 Binder 0.237Hydrogenated Vegetable Oil Coating excipient 0.716 Methacrylic acidCopolymer Type C Coating excipient 0.159 Methacrylic acid Copolymer TypeB Coating excipient 0.318 Malic acid Acidifying agent 0.113 Xanthan gumSuspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.036 Total 7.116

Example 1 Bis. Alternative Formulation

An alternative formulation to the formulation described in Example 1 isdescribed in Example 1bis.

Sodium oxybate immediate release (IR) microparticles were prepared bycoating the IR microparticles described in Example 1 with atop coatlayer. Microparticles were prepared as follows: 170.0 of hydroxypropylcellulose (Klucel™ EF Pharm from Hercules) were solubilized in 4080.0 gof acetone. The solution was entirely sprayed onto 1530.0 g of the IRmicroparticles of Example 1 in a fluid bed spray coater apparatus. IRMicroparticles with volume mean diameter of about 298 microns wereobtained (see Table 1bis-a).

Sodium oxybate modified release (MR) microparticles were prepared asdescribed in example 1 (see Table 1b).

The finished composition, which contains a 50:50 mixture of MR and IRmicroparticles based on their sodium oxybate content, was prepared asfollows: 412.22 g of the above IR microparticles, 530.00 g of the aboveMR microparticles, 29.96 g of malic acid (D/L malic acid), 4.96 g ofxanthan gum (Xantural™ 75 from Kelco), 4.96 g of colloidal silicondioxide (Aerosil™ 200 from Degussa) and 9.92 g of magnesium stearatewere mixed. Individual samples of 7.45 g (corresponding to a 4.5 g doseof sodium oxybate with half of the dose in an immediate-release fractionand half of the dose in a modified release fraction) were weighed (seeTable 1bis-b and 1bis-c).

TABLE 1bis-a Composition of IR Microparticles Quantity per ComponentFunction 2.25 g dose (g) Sodium oxybate Drug substance  2.25Microcrystalline cellulose Core 0.418 spheres Povidone K30 Binder andexcipient in 0.118 diffusion coating Hydroxypropyl cellulose Top coat0.310 Ethyl alcohol Solvent Eliminated during processing Purified waterSolvent Eliminated during processing Acetone Solvent Eliminated duringprocessing Total 3.096

TABLE 1bis-b Qualitative Finished Composition Quantity per ComponentFunction 4.5 g dose (g) MR microparticles Modified release fraction3.981 of sodium oxybate IR microparticles Immediate release fraction3.096 of sodium oxybate Malic acid Acidifying agent 0.225 Xanthan gumSuspending agent 0.037 Colloidal silicon dioxide Gliding agent 0.037Magnesium stearate Lubricant 0.075 Total 7.451

TABLE 1bis-c Quantitative finished composition Quantity per ComponentFunction 4.5 g dose (g) Sodium oxybate Drug substance 4.5Microcrystalline cellulose spheres Core 0.836 Povidone K30 Binder 0.237Hydroxypropyl cellulose Top coat 0.310 Hydrogenated Vegetable OilCoating excipient 0.716 Methacrylic acid Copolymer Type C Coatingexcipient 0.159 Methacrylic acid Copolymer Type B Coating excipient0.318 Malic acid Acidifying agent 0.225 Xanthan gum Suspending agent0.037 Colloidal silicon dioxide Gliding agent 0.037 Magnesium stearateLubricant 0.075 Total 7.451

Compared to the finished composition described in Example 1, thisalternative composition has the following characteristics: same MRmicroparticles, same IR microparticles but with atop coat, increasedamount of malic acid, only one suspending agent (xanthan gum) andpresence of a glidant.

Example 2. In Vivo Pharmacokinetic Study of Finished CompositionAccording to Example 1 (6 q FT218 in Fed and Fasted State)

Pharmacokinetic testing was undertaken in vivo in healthy humanvolunteers. A test product with the finished composition of Example1(FT218) and manufactured at larger scale was administered as a 6 gdose. FT218 was administered to 16 healthy volunteers and a first groupof n=14 was administered FT218 in the fed state and a second group ofn=13 was administered FT218 in the fasted state. The tested samples weremanufactured as described in Table 1c for 4.5 g and quantities werehypothetically adjusted to a 6 g dose. The concentration versus timecurve of FT218 in the fed and fasted state are presented in FIGS. 2A and2B. The derived PK parameters are summarized below in Table 2 and Table3 provides the % ratio of geometric means between the fed and fastedstates. FIG. 2A and Table 3 show a C_(max)(fed)/C_(max)(fasted)=66.7%and an AUC(fed)/AUC(fasted)=86% for FT218. Therefore, the AUC fallswithin the 80-125% bioequivalence range with no effect boundaries, sofood should have no impact on total exposure of the composition. Itappears that food may have no or low impact on MR microparticleabsorption in the latter part of the gastrointestinal tract.

TABLE 2 Mean PK Parameters Tmax Cmax AUC_(0-last) AUC_(0-inf)AUC_(0-8 h) C8h (h) (μg/mL) ± (μg/mL · h) ± (μg/mL · h) ± (μg/mL · h) ±(μg/mL) ± T_(1/2) (h) ± ∧z (/h) ± [min- SD SD SD SD SD SD SD Arm max](CV) (CV) (CV) (CV) (CV) (CV) (CV) FT218 1.5 [0.5- 64.0 ± 241 ± 88.1 242± 88.2 239 ± 85.0 2.09 ± 0.71 ± 1.07 ± fed 2.5] 17.5 (36.5) (36.5)(35.5) 3.14 0.25 0.305 n = 14 (27.3) (150.5) (34.5) (28.5) FT218 0.5390.5 ± 267 ± 85.2 267 ± 85.2 266 ± 82.9 1.43 ± fasted [0.33-1] 15.8(31.9) (32) (31.2) 2.04 n = 13 (17.5) (142.7)

TABLE 3 Food Effect on FT218 PE (fed/fasted) 90% CI C_(max) 66.758.2-76.5 AUC_(0-last) 86.0 79.9-92.6 AUC_(0-inf) 86.1 80.0-92.7

Example 3. Simulated Data to Demonstrate the Food Effect on the IRPortion, MR Portion, and FT218 in the Fed and Fasted State

To illustrate the effect of food on FT218 and the IR and MR portions ofFT218 for a 9 g dosage, concentration versus time curves were simulated.FIG. 3A shows the predicted negative effect of food on the IR portion ofmicroparticles alone at a single 3 g dose. FIG. 3A shows aC_(max)(fed)/C_(max)(fasted)=40% and AUC(fed)/AUC(fasted)=70%. Foodappears to have a similar impact on the IR microparticles of FT218 as onXyrem®, as seen when comparing FIGS. 3A and 4A which shows concentrationversus time curves for Xyrem in the fed and fasted state.

FIG. 3B shows that the predicted negative food effect is reduced in theMR portion of microparticles and in the full FT218 formulation ascompared to the IR portion of microparticles. FIG. 3B shows aC_(max)(fed)/C_(max)(fasted)=55% and an AUC(fed)/AUC(fasted)=80% forFT218. Therefore, it appears that food may have no or low impact on MRmicroparticle absorption in the latter part of the gastrointestinaltract.

Example 4. Comparison of Xyrem® and FT218 in the Fed, 2 hr Post Meal,and Fasted State

The effect of food on FT218 and Xyrem® is shown in FIGS. 4A and 4B. Datawas digitized from the NDA dossier of Xyrem 21-196. FIG. 4A shows aconcentration versus time curve for a 4.5 g single dose of Xyrem® in thefed state, the fasted state and 2 hours post meal. FIG. 4B shows aconcentration versus time curve for a 6 g dose of FT218 in the fedstate, the fasted state and 2 hours post meal. For Xyrem®, C_(max) andAUCs decrease as meal time is closer to administration, while T_(max)increases with food. In comparison, FT218 appears to demonstrate thesame behavior as Xyrem®, but the impact of meal time seems reduced. Fedand 2 h post meal administration appear to have similar PK profiles(inter-study comparison). The derived PK parameters are summarized below(Table 4).

TABLE 4 Mean PK Parameters Xyrem ® (4.5 g) FT218 (6 g) 2 h post 2 h postfast meal^(a) fed fast meal fed T_(max) (h) 0.75 1.25-1.14 2 0.53 [0.33-1.5 [0.33- 1.5 [0.5- 1] 3.5] 2.5] C_(max) 142 ± 88.9-83.0 60.1 ± 90.5 ±64.6 ± 64.0 ± 34.2 20.1 15.8 25.8 17.5 AUC_(0-int) 289 ± 241-233 188 ±267 ± 273 ± 242 ± (μg/mL · h) 109 80 85.2 139 88.2 ^(a)means of studyOMC-SXB-8 are presented.

Example 5. Comparison of Xyrem® and FT218 in the Fed, 2 hr Post Meal,and Fasted State

To compare the effect of food on FT218 and Xyrem® in the fed state, 2hours post-meal, and in the fasted state, the concentration versus timecurves for a 3 g dose of Xyrem® administered twice and a single 6 g doseof FT218 were plotted together.

FIG. 5A shows expected concentration versus time curves for Xyrem® andFT218 in the fed state. Xyrem® in the fed state was extrapolated basedon 4.5 g data from the NDA review of Xyrem® (study OMC-SXB-11)(linearized to the dose of 3 g and multiplied by a factor of correctionof 0.7). As seen in FIG. 5A, Xyrem® risks of lack of efficacy during thefirst dosing, while the onset of efficacy is sooner for FT218 thanXyrem® and the C_(max) of FT218 is below the C_(max) for the 2nd peak ofXyrem®. Therefore, administering FT218 in the fed state may reducesafety concerns associated with administering Xyrem® in the fed state.

FIG. 5B shows expected concentration versus time curves for Xyrem® andFT218 administered two hours post-meal. The Xyrem® data is extrapolatedfrom the PK FT218-1602 BA study. This study was a randomized, 2treatments, 2 periods, 2 sequences cross-over study. The two treatmentswere: FT218 6 g administered 2 hours post evening meal and 2*3 Xyremfirst dose administered 2 hours post evening meal, the 2^(nd) dose wasadministered 4 hours after the first dose. 28 subjects were included.

As seen in FIG. 5B, the C_(max) of FT218 is between the C_(max) of thefirst peak and the C_(max) of the second peak of Xyrem®. Therefore,administering FT218 at two hours post-meal may reduce safety concernsassociated with Xyrem®. FIG. 5C shows expected concentration versus timecurves for Xyrem® and FT218 administered in the fasted state. The Xyrem®data was simulated using numerical superposition.

The impact of the food effect of FT218 is likely reduced on C_(max) andAUCs compared to Xyrem® at the same dose based on food effect and doseproportionality data. The predictability of FT218 may be better thanXyrem®. Table 5 provides expected PK parameters for Xyrem® (2×3 g dose)and FT218 (6 g dose) in the fed state, two hours post-meal, and in thefasted state.

TABLE 5 Estimated PK Parameters Cmax 2^(nd) Tmax (hr) Cmax 1^(st) peakpeak AUC0-inf Xyrem FT218 Xyrem FT218 Xyrem Xyrem FT218 Fed >0.5 1.50<46.4 64.0 ~70.9 <259 242 2 h  0.5 1.50  46.4 64.6  70.9  259 273 postmeal Fast <0.5 0.53 >46.4 90.5 ~70.9 >259 267

Example 6. Comparison of Xyrem® and FT218 in the Fed, 2 hr Post Meal,and Fasted State

To compare the anticipated effect of food on FT218 and Xyrem® in the fedstate, 2 hours post-meal, and in the fasted state, the concentrationversus time curves for a 4.5 g dose of Xyrem® administered twice and asingle 9 g dose of FT218 were plotted together.

FIG. 6A shows expected concentration versus time curves for Xyrem® andFT218 in the fed state. The FT218 data is from a dose proportionalitystudy and the Xyrem® data is from the NDA dossier of Xyrem®.

The FT218 mean concentration-time profile is the observed data of thedose proportionality study at 9 g 2 hours post-meal. As seen in FIG. 6A,Xyrem® risks of lack of efficacy during the first dosing, while theonset of efficacy is sooner for FT218 than Xyrem® and the C_(max) ofFT218 is below the C_(max) for the 2nd peak of Xyrem®. Therefore,administering FT218 in the fed state may reduce safety concernsassociated with administering Xyrem® in the fed state.

FIG. 6B shows expected concentration versus time curves for Xyrem® andFT218 administered two hours post-meal. As seen in FIG. 6B, the C_(max)of FT218 is between the C_(max) of the first peak and the C_(max) of thesecond peak of Xyrem®. Therefore, administering FT218 at two hourspost-meal may reduce safety concerns associated with Xyrem®. FIG. 6Cshows expected concentration versus time curves for Xyrem® and FT218administered in the fasted state. The Xyrem® and FT218 fasted data wasextrapolated based on 4.5 g data (dose linearity assumption andmultiplied by a factor of correction of 1.2).

The impact of the food effect of FT218 is likely reduced on C_(max) andAUCs compared to Xyrem® at the same dose based on food effect and doseproportionality data. The predictability of FT218 may be better thanXyrem®. Table 6 provides expected PK parameters for Xyrem® (2×4.5 gdose) and FT218 (9 g dose) in the fed state, two hours post-meal, and inthe fasted state.

TABLE 6 Estimated PK Parameters Cmax 2^(nd) Tmax (hr) Cmax 1^(st) peakpeak AUC0-inf Xyrem FT218 Xyrem FT218 Xyrem Xyrem FT218 Fed 2 >2 60.1<84.5 ~142 <518 ~518 2 h 1.17^(a)  2 77.6  84.5  142  518 ~518 post mealFast 0.75 <2 142 >84.5 ~142 >518 >518

Example 7. Comparison of Xyrem® and FT218 PK Profiles for AUC and Cmaxin the Fed State

To compare the effect on dosing time, AUC and C_(max) for 6 g of FT218and Xyrem® were plotted over a period of time after eating a meal. FIG.7A shows AUC for 6 g FT218 and 6 g Xyrem® versus time after a meal. FIG.7B shows C_(max) for 6 g FT218 and 6 g Xyrem® versus time after a meal.The PK parameters were calculated on mean PK profiles. Circulatinglevels for FT218 may be more consistent than Xyrem® for each individualthrough the night, as overall the line shape profile for FT218 is moreconstant (fluctuation is reduced). In addition, circulating levels ofGHB may be less impacted by meal (from fed to fast state). For example,taking FT218 during a meal, 1 hour, or 2 hours post-meal may lead tosimilar PK profiles. This may lead to fewer constraints for patients.

Example 8. Pharmacokinetics and Dose Proportionality of FT218 forOnce-Nightly Dosing

To assess the PK of FT218 given as a single dose of 4.5 g, 7.5 g and 9g, compare PK parameters at the 3 doses, and estimate the doseproportionality, an open-label, single-dose, 3-sequential period studyin 20 healthy volunteers was performed. Subjects received 3 separatesingle-dose (without titration) administrations of FT218 at bedtime, twohours post-evening meal, in a sequential order of 4.5 g, 7.5 g and 9 gwith a minimum 7-day washout between doses. Dose proportionality betweenthe three doses was assessed using the power method. Sensitivityanalyses were performed using ANOVA.

Variability of concentrations of FT218 and twice-nightly sodium oxybateIR at 8 h and 10 h post-dose (when patients typically awaken) in the PKpilot and the present study were compared in terms of standarddeviation.

The study was conducted in 20 healthy volunteers (12 males and 8females). All subjects completed periods 1 (4.5 g) and 2 (7.5 g), while12 subjects completed period 3 (9 g).

For the 3 doses, mean pharmacokinetics exhibited similar overallprofiles with median T_(max) between 1.5 and 2 hours (FIG. 8). MeanC_(max) increased from 42.9 to 84.5 μg/mL across the increasing doses.Following C_(max), blood levels gradually decreased overnight. MeanAUC_(inf) was 191, 358 and 443 μg·h/mL for the 4.5, 7.5 and 9 g dosesrespectively. Mean concentrations at 8 hours were 4.8, 19.7 and 25.5μg/mL for the 4.5, 7.5 and 9 g doses respectively.

Table 7 provides variability of concentrations at 8 h and 10 h post-dosefor twice-nightly sodium oxybate and FT218 in the PK pilot and doseproportionality studies.

TABLE 7 Concentrations at 8 h and 10 h post-dose for twice-nightlysodium oxybate and FT218 Twice-nightly FT218 sodium Dose oxybate IR PKpilot study proportionality PK pilot study Part 1-Step 1 Part 2 study PKparameter 2*2.25 g 4.5 g 4.5 g 4.5 g n = 15 n = 14  n = 12  n = 20C_(8 h) mean ± SD (μg/mL) 9.24 ± 11.77 7.40 ± 5.88 6.27 ± 5.81 4.76 ±5.0  BQL set to missing (n = 14) (n = 13) 6.27 ± 5.81 4.76 ± 5.01 BQLset to zero 8.62 ± 11.59 6.87 ± 5.98 C_(10 h) mean ± SD (μg/mL) 2.64 ±3.84  1.21 ± 1.86 0.94 ± 0.55 0.73 ± 0.41 BQL set to missing (n = 8)  (n= 8)  (n = 7) (n = 9) BQL set to zero 1.41 ± 3.04  0.69 ± 1.50 0.55 ±0.63 0.33 ± 0.46 BQL: concentration below quantitation limit.

Mean concentrations at 8 h and 10 h post-dose for FT218 are at least aslow as twice-nightly sodium oxybate IR, regardless of the rule used tohandle concentrations below quantitation limit (Table 7). Moreover, thevariability of the concentrations was similar.

Applying the power method, the slope estimate for C_(max) was 1.02 andthe confidence interval centered on 1.00 (90% C: 0.76-1.28). ForAUC_(inf), the estimate was 1.34 (90% Cl: 1.19-1.48), indicating thatthe increase in the AUC is slightly more than proportional. Theseresults were consistent with ANOVA sensitivity analysis results.

Thirteen subjects (65%) reported a total of 31 treatment emergentadverse events (TEAEs). 8 TEAEs (mainly headache 5/8) were experiencedby 7/20 (35%) subjects during the 4.5 g period. 7 TEAEs (mainlygastrointestinal disorders 4/7) were experienced by 4/20 (20%) subjectsduring the 7.5 g period. 16 TEAEs (mainly gastrointestinal disorders8/16) were experienced by 6/12 (50%) subjects during the 9 g period. Oneof these, a nervous system disorder (sedation) was a SAE. The intensityof TEAEs was judged severe for 2/31 TEAEs (both in 9 g period), moderatefor 10/31 (4 in 4.5 g period, 3 in 7.5 g period and 3 in 9 g period) andmild for 19/31. All the TEAEs were resolved before the end of the study.

FT218 achieved blood-level profiles, when given at bedtime, consistentwith a single CR dose. Dose proportionality was maintained for C_(max)across the dosage range. The safety profile was consistent with what isknown for sodium oxybate and most AEs were mild to moderate in severityeven without titration.

Example 9. TEAEs for FT218 in the Fed and Fasted State

Table 8 provides a summary of the TEAEs in the fed and fasted states fora 6 g dose of FT218.

TABLE 8 Adverse Events with FT218 FT218 6 g single dose FT218 6 g singledose TEAE Fasted (N = 16); n(%) Fed (N = 15); n(%) Somnolence 13 (81.3) 10 (66.7) Dizziness 7 (43.8) 3 (20.0) Nausea 6 (37.5) 1 (6.7) Headache 4(25.0) 2 (13.3) Feeling Drunk 4 (25.0) 4 (26.7) Vomiting 3 (18.8) 1(6.7) Fatigue 3 (18.8) 1 (6.7)

As can be seen from Table 8, administration of 6 g FT218 in the fedstate results in fewer TEAEs than 6 g FT218 administered in the fastedstate.

Moreover, the pharmacokinetic-adverse event (AE) relationship for FT218was evaluated. A total of 129 healthy volunteers received single dosesof FT218 between 4.5-9 g. Six single-dose, randomized, crossover studiesthat assessed the pharmacokinetics of FT218 at 4.5, 6, 7.5 and 9 g inhealthy volunteers were used. Lattice plots, “spaghetti” plots, andscatter plots of individual gamma hydroxybutyrate concentrations andindicators when AEs by system, organ, or class (SOC) were created todetermine any PK-AE relationship.

Most AEs, specifically for the neurological and gastrointestinal SOC,occurred close to T_(max), during the C_(max) period, which for FT218was around 1.5-2 hours after dosing. These AEs were known AEs associatedwith sodium oxybate. There appeared to be no clear correlation betweenindividual plasma GHB concentrations levels and AEs between subjects.Individual AEs were equally distributed above and below the meanpopulation C_(max) and AUC_(inf) for the dataset.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains. It willbe apparent to those skilled in the art that various modifications andvariations may be made in the present invention without departing fromthe scope or spirit of the invention. Other embodiments of the inventionwill be apparent to those skilled in the art from consideration of thespecification and practice of the invention disclosed herein. It isintended that the specification and examples be considered as exemplaryonly, with a true scope and spirit of the invention being indicated bythe following claims.

Numerous examples are provided herein to enhance the understanding ofthe present disclosure. In this regard, a specific set of statements areprovided below characterizing various examples of oral pharmaceuticalcompositions and methods of treatment described herein.

Statement 1: An oral pharmaceutical composition for the treatment ofnarcolepsy, cataplexy, or excessive daytime sleepiness comprisinggamma-hydroxybutyrate in a unit dose suitable for administration lessthan two hours after eating.

Statement 2: The oral pharmaceutical composition of Statement 1, whereinthe composition is suitable for administrating with food, immediatelyafter eating, up to 30 minutes after eating, up to 1 hour after eating,up to 1.5 hours after eating, or up to 2 hours after eating.

Statement 3: The oral pharmaceutical composition of Statements 1 or 2,wherein the composition is administered once daily.

Statement 4: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition is suitable foradministration in the evening.

Statement 5: The oral pharmaceutical composition of any one ofStatements 1-3, wherein the composition is suitable for administrationin the morning.

Statement 6: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition comprisesgamma-hydroxybutyrate in an extended release or delayed releaseformulation.

Statement 7: The oral pharmaceutical composition of any one ofStatements 1-5, wherein the composition comprises gamma-hydroxybutyratein a modified release formulation.

Statement 8: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a substantiallysimilar fed state PK profile and 2 hour post meal administration PKprofile.

Statement 9: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a mean AUC_(inf)when administered less than two hour after eating that is 50%-120% ofthe mean AUC_(inf) when the composition is administered at least twohours after eating.

Statement 10: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a mean AUC_(inf)when administered less than two hour after eating that is 50%-120% ofthe mean AUC_(inf) when the composition is administered while fasting.

Statement 11: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a mean AUC_(inf)when administered less than two hour after eating that is 80%-95% of themean AUC_(inf) when the composition is administered while fasting.

Statement 12: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a mean AUC_(inf)when administered less than two hour after eating that is 85%-90% of themean AUC_(inf) when the composition is administered while fasting.

Statement 13: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a mean C_(max)when administered less than two hour after eating that is 50%-120% ofthe mean C_(max) when the composition is administered at least two hoursafter eating.

Statement 14: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a mean C_(max)when administered less than two hour after eating that is 50%-120% ofthe mean C_(max) when the composition is administered while fasting.

Statement 15: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a mean C_(max)when administered less than two hour after eating that is 55%-80% of themean C_(max) when the composition is administered while fasting.

Statement 16: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a mean C_(max)when administered less than two hour after eating that is 60%-75% of themean C_(max) when the composition is administered while fasting.

Statement 17: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a C_(max) that isdose proportional.

Statement 18: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides no dose dumping.

Statement 19: The oral pharmaceutical composition of any one of thepreceding Statements, wherein there is no significant reduction insafety or efficacy to a patient following administration.

Statement 20: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides an AUC_(inf)bioequivalent to an AUC_(inf) of an equal dose of immediate releaseliquid solution of sodium oxybate administered at t₀ and t_(4h) inequally divided doses at least two hours after eating.

Statement 21: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a C_(max) that isless than the C_(max) of an equal dose of immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses at least two hours after eating.

Statement 22: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a C_(max) that isless than the C_(max) of an equal dose of immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses less than two hours after eating.

Statement 23: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a C_(max) that is10-60% less than the C_(max) of an equal dose of immediate releaseliquid solution of sodium oxybate administered at t₀ and t_(4h) inequally divided doses at least two hours after eating.

Statement 24: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a C_(max) that is10-60% less than the C_(max) of an equal dose of immediate releaseliquid solution of sodium oxybate administered at t₀ and t_(4h) inequally divided doses less than two hours after eating.

Statement 25: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a change inC_(max) between when the composition is administered at least two hoursafter eating and when the composition is administered less than twohours after eating that is 10-60% less than the change in C_(max) of anequal dose of immediate release liquid solution of sodium oxybateadministered at t₀ and t_(4h) in equally divided doses at least twohours after eating.

Statement 26: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides a change inC_(max) between when the composition is administered at least two hoursafter eating and when the composition is administered less than twohours after eating that is 10-60% less than the change in C_(max) of anequal dose of immediate release liquid solution of sodium oxybateadministered at t₀ and t_(4h) in equally divided doses less than twohours after eating.

Statement 27: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides an AUC that ismore dose proportional than the AUC of an equal dose of immediaterelease liquid solution of sodium oxybate administered at t₀ and t_(4h)in equally divided doses at least two hours after eating.

Statement 28: The oral pharmaceutical composition of any one of thepreceding Statements, wherein the composition provides an AUC that ismore dose proportional than the AUC of an equal dose of immediaterelease liquid solution of sodium oxybate administered at t₀ and t_(4h)in equally divided doses less than two hours after eating.

Statement 29: The oral pharmaceutical composition of any one ofStatements 20-28, wherein the equal dose of immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses is Xyrem®.

Statement 30: An oral pharmaceutical composition for the treatment ofnarcolepsy, cataplexy, or excessive daytime sleepiness comprisinggamma-hydroxybutyrate in a unit dose, wherein the absorption of thegamma-hydroxybutyrate in the gastro-intestinal tract is notsubstantially changed by the presence of food.

Statement 31: An oral pharmaceutical composition comprisinggamma-hydroxybutyrate in a unit dose suitable for administration lessthan two hours after eating.

Statement 32: The oral pharmaceutical composition of Statement 31,wherein the composition comprises gamma-hydroxybutyrate in a modifiedrelease formulation.

Statement 33: The oral pharmaceutical composition of Statements 31 or32, wherein the formulation is administered during, immediately after,up to 30 minutes after eating, up to 1 hour after eating, up to 1.5hours after eating, or up to 2 hours after eating.

Statement 34: The oral pharmaceutical composition of any one ofStatements 31-33, wherein the composition is suitable for once-dailyadministration.

Statement 35: The oral pharmaceutical composition of any one ofStatements 31-34, wherein the composition is suitable for administrationin the evening.

Statement 36: The oral pharmaceutical composition of any one ofStatements 31-34, wherein the composition is suitable for administrationin the morning.

Statement 37: The oral pharmaceutical composition of any one ofStatements 31-36, wherein the composition is effective to induce sleepfor at least eight consecutive hours.

Statement 38: The oral pharmaceutical composition of any one ofStatements 31-37, wherein a 6 g dose of the composition administeredless than two hours after eating has a mean AUC_(inf) of greater than230 hr*μg/mL, and a mean C_(max) that is from 50% to 140% of the meanC_(max) provided by an equal dose of immediate release liquid solutionof sodium oxybate administered at t₀ and t_(4h) in equally divided dosesat least two hours after eating.

Statement 39: The oral pharmaceutical composition of Statement 38,wherein the mean C_(max) is from 80% to 140% of the mean C_(max)provided by an equal dose of immediate release liquid solution of sodiumoxybate administered at t₀ and t_(4h) in equally divided doses at leasttwo hours after eating.

Statement 40: The oral pharmaceutical composition of Statement 38,wherein the mean C_(max) is from 100% to 150% of the of the mean C_(max)of a first peak of the equal dose of immediate release liquid solutionof sodium oxybate administered at t₀ and t_(4h) in equally divided dosesat least two hours after eating.

Statement 41: The oral pharmaceutical composition of Statement 38,wherein the mean C_(max) is from 80% to 100% of the of the mean C_(max)of a second peak of the equal dose of immediate release liquid solutionof sodium oxybate administered at t₀ and t_(4h) in equally divided dosesat least two hours after eating.

Statement 42: The oral pharmaceutical composition of Statement 38,wherein the mean C_(max) is about 50 μg/mL to about 82 μg/mL.

Statement 43: The oral pharmaceutical composition of Statement 42,wherein the mean C_(max) is about 64 μg/mL.

Statement 44: The oral pharmaceutical composition of Statement 38,wherein the mean AUC_(inf) is about 242 hr*μg/mL when the formulation isadministered about 30 minutes after eating.

Statement 45: The oral pharmaceutical composition of Statement 38,wherein the mean AUC_(inf) is about 273 hr*μg/mL when the formulation isadministered about 2 hours after eating.

Statement 46: A method of treating narcolepsy and associated disordersand symptoms in a patient in need thereof comprising: administering anoral pharmaceutical composition comprising gamma-hydroxybutyrate lessthan two hours after eating.

Statement 47: The method of Statement 46, wherein the composition isadministered once-daily.

Statement 48: The method of Statement 47, wherein the composition isadministered after eating in the evening.

Statement 49: The method of Statement 47, wherein the composition isadministered after eating in the morning.

Statement 50: The method of any one of Statements 46-49, wherein thecomposition is administered during, immediately after eating, up to 30minutes after eating, up to 1 hour after eating, up to 1.5 hours aftereating, or up to 2 hours after eating.

Statement 51: The method of any one of Statements 46-50, wherein thecomposition is effective to induce sleep for at least six consecutivehours.

Statement 52: The method of any one of Statements 46-51, wherein thecomposition is effective to induce sleep for at least eight consecutivehours.

Statement 53: The method of any one of Statements 46-52, wherein thecomposition is effective to induce sleep for at least ten consecutivehours.

Statement 54: The method of any one of Statements 46-53, wherein thecomposition comprises gamma-hydroxybutyrate in an extended release ordelayed release formulation.

Statement 55: The method of any one of Statements 46-53, wherein thecomposition comprises gamma-hydroxybutyrate in a modified releaseformulation.

Statement 56: The method of any one of Statements 46-55, wherein thecomposition provides a substantially similar fed state PK profile and 2hour post meal administration PK profile.

Statement 57: The method of any one of Statements 46-56, wherein thecomposition provides a mean AUC_(inf) when administered less than twohour after eating that is 50%-120% of the mean AUC_(inf) when thecomposition is administered at least two hours after eating.

Statement 58: The method of any one of Statements 46-57, wherein thecomposition provides a mean AUC_(inf) when administered less than twohour after eating that is 50%-120% of the mean AUC_(inf) when thecomposition is administered while fasting.

Statement 59: The method of any one of Statements 46-58, wherein thecomposition provides a mean AUC_(inf) when administered less than twohour after eating that is 80%-95% of the mean AUC_(inf) when thecomposition is administered while fasting.

Statement 60: The method of any one of Statements 46-59, wherein thecomposition provides a mean AUC_(inf) when administered less than twohour after eating that is 85%-90% of the mean AUC_(inf) when thecomposition is administered while fasting.

Statement 61: The method of any one of Statements 46-60, wherein thecomposition provides a mean C_(max) when administered less than two hourafter eating that is 50%-120% of the mean C_(max) when the compositionis administered at least two hours after eating.

Statement 62: The method of any one of Statements 46-61, wherein thecomposition provides a mean C_(max) when administered less than two hourafter eating that is 50%-120% of the mean C_(max) when the compositionis administered while fasting.

Statement 63: The method of any one of Statements 46-62, wherein thecomposition provides a mean C_(max) when administered less than two hourafter eating that is 55%-80% of the mean C_(max) when the composition isadministered while fasting.

Statement 64: The method of any one of Statements 46-63, wherein thecomposition provides a mean C_(max) when administered less than two hourafter eating that is 60%-75% of the mean C_(max) when the composition isadministered while fasting.

Statement 65: The method of any one of Statements 46-64, wherein thecomposition provides a C_(max) that is dose proportional.

Statement 66: The method of any one of Statements 46-65, wherein thecomposition provides no dose dumping.

Statement 67: The method of any one of Statements 46-66, wherein thereis no significant reduction in safety or efficacy to a patient followingadministration.

Statement 68: The method of any one of Statements 46-67, wherein thecomposition provides an AUC_(inf) bioequivalent to an AUC_(inf) of anequal dose of immediate release liquid solution of sodium oxybateadministered at t₀ and t_(4h) in equally divided doses at least twohours after eating.

Statement 69: The method of any one of Statements 46-68, wherein thecomposition provides a C_(max) that is less than the C_(max) of an equaldose of immediate release liquid solution of sodium oxybate administeredat t₀ and t_(4h) in equally divided doses at least two hours aftereating.

Statement 70: The method of any one of Statements 46-69, wherein thecomposition provides a C_(max) that is less than the C_(max) of an equaldose of immediate release liquid solution of sodium oxybate administeredat t₀ and t_(4h) in equally divided doses less than two hours aftereating.

Statement 71: The method of any one of Statements 46-70, wherein thecomposition provides a C_(max) that is 10-60% less than the C_(max) ofan equal dose of immediate release liquid solution of sodium oxybateadministered at t₀ and t_(4h) in equally divided doses at least twohours after eating.

Statement 72: The method of any one of Statements 46-71, wherein thecomposition provides a C_(max) that is 10-60% less than the C_(max) ofan equal dose of immediate release liquid solution of sodium oxybateadministered at t₀ and t_(4h) in equally divided doses less than twohours after eating.

Statement 73: The method of any one of Statements 46-72, wherein thecomposition provides a change in C_(max) between when the composition isadministered at least two hours after eating and when the composition isadministered less than two hours after eating that is 10-60% less thanthe change in C_(max) of an equal dose of immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses at least two hours after eating.

Statement 74: The method of any one of Statements 46-73, wherein thecomposition provides a change in C_(max) between when the composition isadministered at least two hours after eating and when the composition isadministered less than two hours after eating that is 10-60% less thanthe change in C_(max) of an equal dose of immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses less than two hours after eating.

Statement 75: The method of any one of Statements 46-74, wherein thecomposition provides an AUC that is more dose proportional than the AUCof an equal dose of immediate release liquid solution of sodium oxybateadministered at t₀ and t_(4h) in equally divided doses at least twohours after eating.

Statement 76: The method of any one of Statements 46-75, wherein theequal dose of immediate release liquid solution of sodium oxybateadministered at to and t₄ h in equally divided doses is Xyrem®.

Statement 77: The method of any one of Statements 46-76, wherein a 6 gdose of the composition administered has been shown to achieve a meanAUC_(inf) of greater than 230 hr*μg/mL, and a mean C_(max) that is from50% to 140% of the mean C_(max) provided by an equal dose of immediaterelease liquid solution of sodium oxybate administered at t₀ and t_(4h)in equally divided doses at least two hours after eating.

Statement 78: The method of Statement 77, wherein the mean C_(max) isfrom 80% to 140% of the mean C_(max) provided by an equal dose ofimmediate release liquid solution of sodium oxybate administered at t₀and t_(4h) in equally divided doses approximately two hours aftereating.

Statement 79: The method of any one of Statements 77-78, wherein themean C_(max) is from 100% to 150% of the of the mean C_(max) of a firstpeak of the equal dose of immediate release liquid solution of sodiumoxybate administered at t₀ and t_(4h) in equally divided doses at leasttwo hours after eating.

Statement 80: The method of any one of Statements 77-79, wherein themean C_(max) is from 80% to 100% of the of the mean C_(max) of a secondpeak of the equal dose of immediate release liquid solution of sodiumoxybate administered at t₀ and t_(4h) in equally divided dosesapproximately two hours after eating.

Statement 81: The method of any one of Statements 77-80, wherein themean C_(max) is about 50 μg/mL to about 82 μg/mL.

Statement 82: The method of Statement 81, wherein the mean C_(max) isabout 64 μg/mL.

Statement 83: The method of any one of Statements 77-82, wherein themean AUC_(inf) is about 242 hr*μg/mL when the formulation isadministered about 30 minutes after eating.

Statement 84: The method of any one of Statements 77-82, wherein themean AUC_(inf) is about 273 hr*μg/mL when the formulation isadministered about 2 hours after eating.

Statement 85: An oral pharmaceutical composition for the treatment ofnarcolepsy, cataplexy, or excessive daytime sleepiness comprisinggamma-hydroxybutyrate in a unit dose suitable for administration oncedaily, wherein the composition is dose proportional.

Statement 86: The oral pharmaceutical composition of Statement 85,wherein the composition is suitable for administration in the evening.

Statement 87: The oral pharmaceutical composition of Statement 85,wherein the composition is suitable for administration in the morning.

Statement 88: The oral pharmaceutical composition of any one ofStatements 85-87, wherein the composition is dose proportional across4.5 g, 7.5 g, and 9 g doses of the composition.

Statement 89: The oral pharmaceutical composition of any one ofStatements 85-88, wherein the C_(max) of the composition is proportionalacross 4.5 g, 7.5 g, and 9 g doses of the composition.

Statement 90: The oral pharmaceutical composition of any one ofStatements 85-89, wherein the composition is dose proportional by afactor of 1 to 1.3.

Statement 91: The oral pharmaceutical composition of any one ofStatements 88-90, wherein median T_(max) is between about 1.5 and 2hours across the increasing doses.

Statement 92: The oral pharmaceutical composition of any one ofStatements 88-97, wherein the mean C_(max) is between about 42.9 and84.5 μg/mL across the increasing doses.

Statement 93: The oral pharmaceutical composition of any one ofStatements 88-92, wherein the mean AUC_(inf) is about 191, 358 and 443μg·h/mL for the 4.5, 7.5 and 9 g doses respectively.

Statement 94: The oral pharmaceutical composition of any one ofStatements 88-93, wherein the mean concentrations at 8 hours are about4.8, 19.7 and 25.5 μg/mL for the 4.5, 7.5 and 9 g doses respectively.

Statement 95: A method of treating narcolepsy and associated disordersand symptoms in a patient in need thereof comprising: administering anoral pharmaceutical composition comprising gamma-hydroxybutyrate oncedaily, wherein the composition is dose proportional.

Statement 96: The method of Statement 95, wherein the composition isadministered in the evening.

Statement 97: The method of Statement 95, wherein the composition isadministered in the morning.

Statement 98: The method of any one of Statements 95-97, wherein thecomposition is dose proportional across 4.5 g, 7.5 g, and 9 g doses ofthe composition.

Statement 99: The method of any one of Statements 95-98, wherein theC_(max) of the composition is proportional across 4.5 g, 7.5 g, and 9 gdoses of the composition.

Statement 100: The method of any one of Statements 95-99, wherein thecomposition is dose proportional by a factor of 1 to 1.3.

Statement 101: The method of any one of Statements 98-100, whereinmedian T_(max) is between about 1.5 and 2 hours across the increasingdoses.

Statement 102: The method of any one of Statements 98-101, wherein themean C_(max) is between about 42.9 and 84.5 μg/mL across the increasingdoses.

Statement 103: The method of any one of Statements 98-102, wherein themean AUC_(inf) is about 191, 358 and 443 μg·h/mL for the 4.5, 7.5 and 9g doses respectively.

Statement 104: The method of any one of Statements 98-103, wherein themean concentrations at 8 hours are about 4.8, 19.7 and 25.5 μg/mL forthe 4.5, 7.5 and 9 g doses respectively.

Statement 105: An oral pharmaceutical composition for the treatment ofnarcolepsy, cataplexy, or excessive daytime sleepiness comprisinggamma-hydroxybutyrate in a unit dose suitable for administration oncedaily, wherein most adverse events (AEs) occur close to T_(max), duringthe C_(max) period.

Statement 106: The oral pharmaceutical composition of Statement 105,wherein most AEs occur 1.5-2 hours after dosing.

Statement 107: The oral pharmaceutical composition of Statements 105 or106, wherein administration of the oral pharmaceutical composition lessthan two hours after eating results in fewer AEs than administration ofthe oral pharmaceutical composition at least two hours after eating.

Statement 108: The oral pharmaceutical composition of any one ofStatements 105-107, wherein the oral pharmaceutical composition has amore favorable safety profile as compared to an equal dose of immediaterelease liquid solution of sodium oxybate administered at t₀ and t_(4h)in equally divided doses.

Statement 109: The oral pharmaceutical composition of any one ofStatements 105-108, wherein administration of the oral pharmaceuticalcomposition once daily results in fewer AEs than administration of anequal dose of immediate release liquid solution of sodium oxybateadministered at t₀ and t_(4h) in equally divided doses.

Statement 110: A method of treating narcolepsy and associated disordersand symptoms in a patient in need thereof comprising: administering anoral pharmaceutical composition comprising gamma-hydroxybutyrate oncedaily, wherein most AEs occur close to T_(max), during the C_(max)period.

Statement 111: The method of Statement 110, wherein most AEs occur 1.5-2hours after dosing.

Statement 112: The method of Statements 110 or 111, whereinadministration of the oral pharmaceutical composition less than twohours after eating results in fewer AEs than administration of the oralpharmaceutical composition at least two hours after eating.

Statement 113: The method of any one of Statements 110-112, wherein theoral pharmaceutical composition has a more favorable safety profile ascompared to an equal dose of immediate release liquid solution of sodiumoxybate administered at t₀ and t_(4h) in equally divided doses.

Statement 114: The method of any one of Statements 110-113, whereinadministration of the oral pharmaceutical composition once daily resultsin fewer AEs than administration of an equal dose of immediate releaseliquid solution of sodium oxybate administered at t₀ and t_(4h) inequally divided doses.

Statement 115: The method of any one of Statements 110-114, wherein theamount of AEs are reduced over an 8 hour, 12 hour, 16 hour, 20 hour, 24hour, and/or 48 hour time period following administration of the oralpharmaceutical composition, as compared to an equal dose of an immediaterelease sodium oxybate formulation administered more frequently thanonce-daily.

Statement 116: A method of reducing the amount of adverse events (AEs)in a patient with narcolepsy, cataplexy, or excessive daytime sleepinesscomprising: administering an oral pharmaceutical composition comprisinggamma-hydroxybutyrate once daily, wherein the gamma-hydroxybutyratecomposition has fewer C_(max) periods than an equal dose of immediaterelease sodium oxybate formulation administered more frequently thanonce-daily.

Statement 117: The method of Statement 116, wherein administration ofthe gamma-hydroxybutyrate composition results in fewer adverse eventsand fewer C_(max) periods over an 8 hour, 12 hour, 16 hour, 20 hour, 24hour, and/or 48 hour time period, as compared to the immediate releasesodium oxybate formulation administered more frequently than once-daily.

Statement 118: The method of Statements 116 or 117, wherein thegamma-hydroxybutyrate composition has a superior safety profile comparedto the immediate release sodium oxybate formulation administered morefrequently than once-daily.

What is claimed is:
 1. An oral pharmaceutical composition for thetreatment of narcolepsy, cataplexy, or excessive daytime sleepinesscomprising gamma-hydroxybutyrate in a unit dose suitable foradministration less than two hours after eating.
 2. The oralpharmaceutical composition of claim 1, wherein the composition issuitable for administrating with food, immediately after eating, up to30 minutes after eating, up to 1 hour after eating, up to 1.5 hoursafter eating, or up to 2 hours after eating.
 3. The oral pharmaceuticalcomposition of claim 1, wherein the composition is administered oncedaily.
 4. The oral pharmaceutical composition of claim 1, wherein thecomposition is suitable for administration in the evening.
 5. The oralpharmaceutical composition of claim 1, wherein the composition issuitable for administration in the morning.
 6. The oral pharmaceuticalcomposition of claim 1, wherein the composition comprisesgamma-hydroxybutyrate in an extended release or delayed releaseformulation.
 7. The oral pharmaceutical composition of claim 1, whereinthe composition comprises gamma-hydroxybutyrate in a modified releaseformulation.
 8. The oral pharmaceutical composition of claim 1, whereinthe composition provides a substantially similar fed state PK profileand 2 hour post meal administration PK profile.
 9. The oralpharmaceutical composition of claim 1, wherein the composition providesa mean AUC_(inf) when administered less than two hour after eating thatis 50%-120% of the mean AUC_(inf) when the composition is administeredat least two hours after eating.
 10. The oral pharmaceutical compositionof claim 1, wherein the composition provides a mean AUC_(inf) whenadministered less than two hour after eating that is 50%-120% of themean AUC_(inf) when the composition is administered while fasting. 11.The oral pharmaceutical composition of claim 10, wherein the compositionprovides a mean AUC_(inf) when administered less than two hour aftereating that is 80%-95% of the mean AUC_(inf) when the composition isadministered while fasting.
 12. The oral pharmaceutical composition ofclaim 11, wherein the composition provides a mean AUC_(inf) whenadministered less than two hour after eating that is 85%-90% of the meanAUC_(inf) when the composition is administered while fasting.
 13. Theoral pharmaceutical composition of claim 1, wherein the compositionprovides a mean C_(max) when administered less than two hour aftereating that is 50%-120% of the mean C_(max) when the composition isadministered at least two hours after eating.
 14. The oralpharmaceutical composition of claim 1, wherein the composition providesa mean C_(max) when administered less than two hour after eating that is50%-120% of the mean C_(max) when the composition is administered whilefasting.
 15. The oral pharmaceutical composition of claim 14, whereinthe composition provides a mean C_(max) when administered less than twohour after eating that is 55%-80% of the mean C_(max) when thecomposition is administered while fasting.
 16. The oral pharmaceuticalcomposition of claim 15, wherein the composition provides a mean C_(max)when administered less than two hour after eating that is 60%-75% of themean C_(max) when the composition is administered while fasting.
 17. Theoral pharmaceutical composition of claim 1, wherein the compositionprovides a C_(max) that is dose proportional.
 18. The oralpharmaceutical composition of claim 1, wherein the composition providesno dose dumping.
 19. The oral pharmaceutical composition of claim 1,wherein there is no significant reduction in safety or efficacy to apatient following administration.
 20. The oral pharmaceuticalcomposition of claim 1, wherein the composition provides an AUC_(inf)bioequivalent to an AUC_(inf) of an equal dose of immediate releaseliquid solution of sodium oxybate administered at t₀ and t_(4h) inequally divided doses at least two hours after eating.
 21. The oralpharmaceutical composition of claim 1, wherein the composition providesa C_(max) that is less than the C_(max) of an equal dose of immediaterelease liquid solution of sodium oxybate administered at t₀ and t_(4h)in equally divided doses at least two hours after eating.
 22. The oralpharmaceutical composition of claim 1, wherein the composition providesa C_(max) that is less than the C_(max) of an equal dose of immediaterelease liquid solution of sodium oxybate administered at t₀ and t_(4h)in equally divided doses less than two hours after eating.
 23. The oralpharmaceutical composition of claim 1, wherein the composition providesa C_(max) that is 10-60% less than the C_(max) of an equal dose ofimmediate release liquid solution of sodium oxybate administered at t₀and t_(4h) in equally divided doses at least two hours after eating. 24.The oral pharmaceutical composition of claim 1, wherein the compositionprovides a C_(max) that is 10-60% less than the C_(max) of an equal doseof immediate release liquid solution of sodium oxybate administered att₀ and t_(4h) in equally divided doses less than two hours after eating.25. The oral pharmaceutical composition of claim 1, wherein thecomposition provides a change in C_(max) between when the composition isadministered at least two hours after eating and when the composition isadministered less than two hours after eating that is 10-60% less thanthe change in C_(max) of an equal dose of immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses at least two hours after eating.
 26. The oralpharmaceutical composition of claim 1, wherein the composition providesa change in C_(max) between when the composition is administered atleast two hours after eating and when the composition is administeredless than two hours after eating that is 10-60% less than the change inC_(max) of an equal dose of immediate release liquid solution of sodiumoxybate administered at t₀ and t_(4h) in equally divided doses less thantwo hours after eating.
 27. The oral pharmaceutical composition of claim1, wherein the composition provides an AUC that is more doseproportional than the AUC of an equal dose of immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses at least two hours after eating.
 28. The oralpharmaceutical composition of claim 1, wherein the composition providesan AUC that is more dose proportional than the AUC of an equal dose ofimmediate release liquid solution of sodium oxybate administered at t₀and t_(4h) in equally divided doses less than two hours after eating.29. An oral pharmaceutical composition comprising gamma-hydroxybutyratein a unit dose suitable for administration less than two hours aftereating.